I. Desired endpoint for the treatment of chronic hepatitis B (CHB) There are three efficacy goals for nucleoside (acid) analogs for the treatment of chronic hepatitis B. The first goal is to reduce hepatitis B virus (HBV) to below detectable levels, which is a therapeutic goal that must be achieved because nucleoside (acid) analogs target HBV DNA polymutase or reverse transcriptase, otherwise they are susceptible to drug resistance (which is clearly correlated with efficacy). However, obtaining this response still requires continued treatment, and relapse rates are high once the drug is discontinued. The second goal is hepatitis B virus e antigen (HBeAg) serologic conversion, which has the colloquial term of having achieved a silver medal, but achieving this treatment goal still has a high relapse rate even after a period of consolidation. The third goal is hepatitis B virus s-antigen (HBsAg) clearance, as HBsAg is closely related to covalent closed-loop DNA (cccDNA). The latter is the transcriptional template of HBV and serves as a reservoir for intrahepatic HBV, while HBsAg is the replication product of HBV cccDNA, the level of which reflects the transcriptional activity of cccDNA. Therefore, the main challenge of anti-HBV therapy is to clear intrahepatic cccDNA and achieve HBsAg clearance. The long-term goal of CHB treatment is to reduce the incidence of cirrhosis and hepatocellular carcinoma, and HBsAg clearance can minimize the risk of cirrhosis and hepatocellular carcinoma and is considered to be It is considered to be close to a “cure”. The results of the study showed that the annual incidence of liver cancer in patients treated until HBV DNA alone was below the lower limit of detection was 0.1%, while that in those with HBsAg clearance was only 0.02%, a fivefold decrease compared to the former (Figure 1). The American Association for the Study of Liver Diseases (AASLD) guidelines recommend that HBeAg-positive (commonly known as “major triple-positive”) patients with HBeAg seroconversion and undetectable HBV DNA on NA therapy should continue to consolidate treatment for 6 months before considering discontinuation of the drug, while the European Association for the Study of Liver Diseases (EASL) and the Asia-Pacific Liver Study (APLS) recommend that patients with HBeAg-positive (commonly known as “major triple-positive”) should continue to consolidate treatment for 6 months before considering discontinuation of the drug. EASL and APASL guidelines recommend 12 months of treatment consolidation. For HBeAg-negative patients treated with NA, the APASL guidelines recommend a minimum of 2 years on the drug with no HBV DNA testing up to 3 times, each 6 months apart, while the EASL and AASLD do not recommend discontinuation of the drug unless HBsAg clearance occurs. In fact, application of lamivudine (LAM), adefovir (ADV) or telbivudine (LdT) for 1 year resulted in rare HBsAg clearance, application of entecavir (ETV) for 1 and 2 years resulted in HBsAg clearance of 2% and 5%, and application of tenofovir (TDF) for 1, 2 and 5 years resulted in HBsAg clearance of 3%, 8% and 10%, respectively. Studies have shown that most HBeAg-positive patients treated with NA only temporarily undergo HBeAg serologic conversion, with a higher rate of virologic relapse after discontinuation, and some experience HBeAg serologic reversal and hepatitis exacerbation, especially in those who achieve HBeAg serologic conversion with NA treatment before the age of 30, with a significantly higher relapse rate after discontinuation of NA than in those with spontaneous HBeAg serologic conversion. HBeAg-negative patients are extremely difficult to achieve HBsAg clearance, and even after 5 years of treatment with potent TDF, HBsAg clearance has not been observed to occur in those who have been treated. However, the results of a study in Athens were very positive: 33 HBeAg-negative patients were treated with ADV for 4-5 years, and after long-term follow-up after discontinuation of the drug, 18 patients achieved a sustained response, 13 of whom cleared HBsAg, and another 15 patients relapsed and were retreated with NA, and HBsAg clearance occurred in one case, and lower HBsAg levels at the end of treatment were significantly correlated with HBsAg clearance correlated. In another study, 32 HBeAg-negative patients who discontinued NA were followed for 24 months, and 9 of them without relapse had HBsAg levels <1000 IU/mL at the end of treatment; during the follow-up period, HBsAg levels continued to decrease, and HBsAg clearance occurred in 6 of them. Therefore, HBsAg levels (<1000 IU/mL) can be used as a criterion for NA discontinuation in HBeAg-negative patients maintaining undetectable HBV DNA. A study in Taiwan, China, showed that the cumulative relapse rate 1 year after ETV discontinuation was significantly lower than that of LAM or LdT discontinuers, and relapse occurred later, and in addition, the cumulative relapse rate of patients with baseline serum HBVDNA ≤2×105 IU/mL was significantly lower than that of patients with HBV DNA >2×105 IU/mL (P=0.036). However, the results of a study conducted by Chang (Chaung) et al. in Asian CHB patients showed that 90% of patients on nucleoside analogs relapsed after discontinuation of the drug even after they had achieved HBV DNA suppression, HBeAg serologic conversion, and received consolidation therapy (Figure 2). The key to CHB treatment is to help the body achieve immune control through drug therapy. Only by suppressing viral replication while enhancing/restoring HBV-specific T-cell activity through positive and negative immune regulation can HBV infection be controlled and the goal of clinical cure be achieved. The difference in the effect of different antiviral drugs on the body’s HBV immune response is the main reason for the difference in efficacy. Nucleoside analogs have a single target of action, and although they can briefly restore immune function by inhibiting HBV DNA, patients are prone to relapse after discontinuation (Figure 3), because nucleoside analogs can effectively inhibit viral replication, but it is difficult to achieve safe discontinuation because of the lack of immunomodulatory effects. In view of the above, some experts suggest the following discontinuation criteria: 1. All patients who have achieved HBsAg clearance can discontinue NA; 2. HBeAg-positive patients who have achieved HBeAg serological conversion and undetectable HBV DNA need to consolidate treatment for at least 9-12 months; 3. HBeAg-negative patients who have been treated for at least 2 years and When reaching undetectable HBVDNA and very low HBsAg titers, further studies are needed to confirm whether the drug can be discontinued; 4. For patients with cirrhosis, it is not advisable to discontinue the drug unless HBsAg clearance occurs to avoid the risk of hepatitis attack and liver failure. Can discontinuation be considered for patients who have been treated for a long time with unsatisfactory efficacy, such as drug-resistant and poor responders? There is no clear opinion yet. In my personal clinical experience, if a patient with chronic hepatitis B has a poor response, often with a high viral load, it is difficult to achieve the first efficacy goal with current drugs. If long-term treatment is still not achieved with undetectable HBV DNA, you can consider discontinuing the drug for observation, otherwise it is very easy to cause drug resistance. After discontinuation of the drug, in accordance with the management of slow hepatitis B, timely testing of relevant indicators: if there is a significant rebound of biochemical indicators (immunological response), the treatment may be given again to improve the efficacy; if the patient only virological rebound but not biochemical indicators rebound, long-term follow-up can be given with reference to chronic HBV carriers. Of course, there is no more authoritative clinical evidence on whether the apparent rebound of biochemical indicators will improve the efficacy, but it is worth further observation. On the other hand, in the case of cirrhotic patients, oral antiviral drugs should not be discontinued regardless of their efficacy, as there have been many blood lessons.