In chronic hepatitis B virus infection, chronic hepatitis B virus infection can be divided into four phases according to the HBV virological, serological and clinical biochemical manifestations of the patient: the immune tolerance phase is characterized by high serum HBV DNA levels, high HBeAg levels and normal ALT levels; the immune clearance phase is characterized by positive HBV DNA and HBeAg and abnormal ALT levels; the immune control The immune control phase is characterized by low HBV replication, HBeAg negative and anti-HBe positive, and persistently normal ALT levels; after the immune control phase, some patients enter the hepatitis reactivation phase due to HBV gene mutation and the absence of HBeAg production (HBeAg negative), and evade the host’s immune control and re-emerge with HBV replication and ALT elevation, which is manifested by serum HBV DNA This phase is characterized by positive serum HBV DNA, negative HBeAg and elevated ALT levels. Patients in this phase are also called HBeAg-negative chronic hepatitis B because of HBeAg-negative and inflammatory activity of the liver. Patients are candidates for antiviral therapy due to the immune clearance and reactivation phases with inflammation of the liver and progression of the disease. Compared to HBeAg-positive chronic hepatitis B, the clinical features of HBeAg-negative chronic hepatitis B are: relatively low serum HBV DNA levels and HBsAg levels; liver inflammation may be more pronounced and liver disease more severe; hepatitis rarely remits spontaneously; and relapse often occurs after discontinuation of antiviral therapy. Currently, nucleoside (acid) analogue antiviral therapy for HBeAg-negative hepatitis requires long-term maintenance therapy, and the only indicator of whether or not to discontinue therapy after interferon treatment is the degree of HBsAg decline and HBsAg levels. For HBeAg-negative chronic hepatitis B, the European liver disease guidelines state that the only opportunity to achieve discontinuation of antiviral therapy in HBeAg-negative patients is currently with interferon therapy. However, in clinical practice, not every patient can achieve non-relapse with interferon therapy. Therefore, how to make HBeAg-negative patients non-relapse after treatment discontinuation, criteria for discontinuation, how to predict early whether patients can achieve discontinuation criteria and how to make more patients achieve discontinuation criteria are the focus of current clinical research, and what every patient and clinician would like to know most. As clinical research on antiviral therapy for chronic hepatitis B progresses, guidelines for the treatment of chronic hepatitis B in the United States, Europe, and the Asia Pacific Annual Meeting on Liver Disease all point to durable immune control after treatment as a treatment endpoint and goal. Durable immune control is demonstrated by patients having long-term serum HBV DNA negativity or low levels, long-term HBeAg seroconversion, or even HBsAg disappearance/seroconversion after cessation of drug therapy. The results of numerous studies show that patients who obtain immune control have long-term good clinical outcomes and reduced incidence of cirrhosis, liver failure and hepatocellular carcinoma. 1. Immunocontrol is a key factor in determining whether HBeAg-negative patients relapse after discontinuation of antiviral therapy. HBeAg-negative chronic hepatitis B occurs on the basis of HBV gene mutation and absence of HBeAg production (HBeAg-negative) and evasion of host immune control, re-emergence of HBV replication and hepatitis reactivation. The reason why nucleoside (acid) analogue therapy cannot be discontinued is because it merely inhibits viral replication without improving the patient’s immune clearance of HBV. In contrast, interferon therapy both directly inhibits viral replication and, more importantly, clears virally infected hepatocytes through its immunomodulatory effects to regain immune control. The basis of immune control is the clearance of virus-infected liver cells to a certain extent through interferon therapy and the ability to continue to inhibit viral replication and maintain quiescence of liver inflammation after drug discontinuation. Therefore, durable immune control is the key to non-relapse after discontinuation of antiviral therapy in HBeAg-negative patients and is the goal of antiviral therapy. 2. The decrease in serum HBsAg levels during treatment is a marker reflecting the clearance of virally infected hepatocytes. The role of immune control in the treatment of patients with chronic hepatitis B has led many researchers to hope to find a specific immunological indicator that reflects the immune control of HBV after interferon therapy, but so far there is no immunological indicator that can truly reflect the immune control of HBV. However, whatever the immunological index, it is ultimately reflected in the clearance of virally infected hepatocytes and the extent of their clearance. Since HBV cccDNA is in the nucleus of hepatocytes and coexists with hepatocytes, and is significantly correlated with serum HBsAg level, therefore, HBsAg level and the degree of decrease can reflect the clearance of virus-infected hepatocytes, which is an important indicator to evaluate whether there is immune control and clinical efficacy detection index. 3. Strategies to improve immune control of interferon therapy in HBeAg-negative patients. In the treatment of patients with chronic hepatitis B, any drug to obtain better efficacy depends on the patient’s immune strength against HBV, the stronger the immune clearance, the higher the degree and ability of immune control in the treatment of interferon, immune control will be more durable, and even the elimination of HBsAg. to make more patients obtain immune control through interferon therapy, it is necessary to start from the following places. ① Careful study of the clinical characteristics of patients before treatment to select superior patients. The results of a large number of studies have shown that, in addition to immunological indicators, other clinical indicators can indirectly reflect that patients have better immunity and correlate with the efficacy of interferon therapy. The results of the study showed that superior patients for interferon therapy can be selected based on the characteristics of other clinical indicators of patients, among which in HBeAg-negative chronic hepatitis B patients, the age of patients, serum ALT levels, low HBV DNA levels, especially low HBsAg levels based on low HBV DNA levels are most important. In young people, high ALT levels or those with histological evidence of significant liver inflammation and low HBsAg levels on the basis of low HBV DNA levels, interferon should be preferred in the absence of contraindications to interferon therapy. ② Timely evaluation of efficacy in treatment. The only evaluation indicators of interferon therapy in HBeAg-negative chronic hepatitis B patients are serum HBV DNA levels and HBsAg levels. Although the change of HBV DNA level and the decrease of HBsAg level during treatment can reflect the efficacy, more literature shows that the decrease of HBsAg level is more valuable, but the decrease of HBsAg must be based on the decrease of HBV DNA. Those without HBV DNA decline should change their treatment strategy even if there is a decline in HBsAg levels. Although the greater the decrease in HBsAg levels at 12 weeks, the higher the rate of sustained viral response after 48 weeks of treatment, some patients have a significant decrease in HBsAg only at 24 weeks of treatment; therefore, if the decrease in HBsAg at 12 weeks of treatment is not satisfactory, it is considered that Therefore, if patients are not considered to have achieved durable immune control based on unsatisfactory HBsAg decline at 12 weeks of treatment, some patients with unsatisfactory decline at 12 weeks but good decline at 24 weeks will lose the opportunity to gain immune control by abandoning treatment. It is worth noting that in addition to the absolute value of HBsAg levels at 24 weeks of treatment for judgment and prediction, the magnitude of decline should be evaluated because the baseline HBsAg before treatment varies for each patient and the magnitude of decline may better reflect the degree of clearance of virally infected cells during the patient’s treatment. It has been shown that a 1 log IU/ml decrease in HBsAg from baseline at 24 weeks of treatment predicts a higher rate of sustained viral response through 48 weeks of treatment. Patients with >10% reduction in HBsAg levels from baseline at 24 weeks of treatment had sustained viral response rates of 43.3% and 35.8% 1 and 5 years after stopping treatment, respectively, while those with <10% reduction had sustained response rates of only 13.3%. The absence of significant decreases in HBsAg during treatment, although not high in absolute values, indicates that interferon therapy has not resulted in further clearance of the patient's virally infected hepatocytes and that the treatment strategy should be changed. Although abnormal ALT often indicates that patients have liver inflammation, and its elevated levels in most untreated and nucleoside (acid) analogues indicate the presence or exacerbation of liver inflammation, there is no evidence that elevated ALT during interferon therapy is associated with increased liver inflammation, and there is more evidence that patients with elevated ALT during interferon therapy will have a better response. (iii) The role of proper understanding of the relationship between serum HBV DNA levels and HBsAg levels in predicting immune control. Immune control in the natural HBV infection state and interferon therapy is reflected by the clearance of infected cells and the degree of clearance, which in turn is reflected in the decline of hepatic cccDNA and changes in serum HBsAg levels. the replication of HBV DNA can replenish the pool of cccDNA in hepatocytes, and although the correlation between serum HBV DNA levels in the natural infection state and Although the correlation between serum HBV DNA levels and HBsAg levels is poor in the natural state of infection, in order to obtain durable immune control of the virus in interferon therapy, both HBV DNA and HBsAg must be declined. for HBsAg decline without achieving HBV DNA transitions may also not achieve durable immune control, and similarly, only HBV DNA transitions without HBsAg levels declining to a certain value are It is difficult to obtain immune control. ④ Do not take "course of treatment" as the end of treatment. The endpoint of treatment is the patient's ability to maintain durable viral replication inhibition, HBeAg serological conversion or HBsAg disappearance after discontinuation of drug therapy, i.e. durable immune control. Although the duration of interferon therapy for patients with chronic hepatitis B is 48 weeks in some drug instructions for interferon, that does not indicate that the patient needs only 48 weeks of therapy or that the duration of therapy is 48 weeks. The duration of therapy in the instructions was determined by the design of the clinical trials of the drug before it was marketed at the time, but in clinical practice, obtaining immune control has become the goal of antiviral therapy for chronic hepatitis B. The basis of immune control is determined by the degree of clearance of virally infected cells after interferon therapy and the ability of immunity to continue to inhibit viral replication and continue to clear hepatocytes after cessation of therapy. In patients with chronic hepatitis B treated with interferon, the clearance half-life of virally infected hepatocytes is 2.7-75 days, which means that the time required to achieve immune control varies greatly from patient to patient. Patients who have a better response within 48 weeks of treatment but do not achieve the goal of immune control should not be discontinued just because they have been treated for 48 weeks; premature discontinuation will deprive these patients of the opportunity to achieve immune control. They should be treated for a longer period of time. The Chinese study showed that the sustained viral response rate and HBsAg disappearance rate at 72 weeks of treatment were 88.9% and 30.6%, respectively, significantly higher than the 63.3% and 13.3% at 48 weeks. In genotype D patients, the sustained viral response rate at 48 weeks of treatment was only 12%, significantly lower than the 29% at 96 weeks of treatment, and there was a 6% HBsAg disappearance rate at 96 weeks of treatment, while no HBsAg disappearance occurred at 48 weeks of treatment. ⑤ Gradually pursue higher immune control goals. For HBeAg-negative chronic hepatitis B, the indexes that can reflect the antiviral efficacy are the decrease of serum HBV DNA and HBsAg decrease, in order to achieve immune control, there should first be the conversion of HBV DNA, and the decrease of HBsAg on the basis of HBV DNA conversion is possible to obtain lasting immune control. The faster HBsAg decreases during treatment and the greater the decrease, the higher the chance of obtaining immune control. However, the amount of HBsAg decline needed to imply immune control, i.e., the ability to maintain a sustained viral response after drug discontinuation. Different studies have different answers. Some studies show that patients who bring HBsAg down to less than 1000 IU/ml will have a sustained viral response, but others show that patients with HBsAg levels below 100 IU/ml will have a good long-term prognosis. Patients with HBsAg <10 IU/ml at the end of treatment maintained HBV DNA response in 85% of patients 1 year after discontinuation of the drug. The variation in results from study to study may be due to the different baselines of patients in different studies. However, in clinical work, higher goals should be pursued progressively for treated individuals. Treatment should not be ended just because a patient's HBsAg level has dropped to the point where a sustained viral response can be reached, because as long as HBsAg is present, it means that the patient can still undergo activation of HBV DNA replication and eventually develop hepatitis. In the results of a long-term follow-up study of patients with chronic HBV infection, it was shown that the only indicator of a good long-term outcome for the patient was the disappearance of HBsAg. The incidence of hepatocellular carcinoma and cirrhosis was zero in patients who obtained the disappearance of HBsAg before the development of cirrhosis. Therefore, patients whose HBsAg levels continue to decline during clinical treatment should continue treatment so that they have the greatest chance of obtaining HBsAg disappearance. For those whose HBsAg levels continue to decline during treatment, the course of treatment should be extended to achieve the ideal treatment endpoint of HBsAg disappearance. In a study by Li Minghui et al, extended treatment for those with negative HBV DNA and HBsAg levels below 200 IU/ml at 48 weeks of treatment increased the rate of HBsAg disappearance from 7.2% to 14.5% at 48 weeks. 4. Current issues that still need to be addressed. Although the degree of decline in HBsAg levels and the absolute values achieved have great predictive power for durable immune control, it is still not possible to clearly predict the HBsAg cut-off value for durable immune control, and the time that durable immune control can be maintained. How to achieve durable immune control for those who have not significantly decreased HBsAg levels during the course of treatment although HBV DNA has significantly decreased and turned negative. How to determine the efficacy, whether to extend the treatment and at what point to change the treatment regimen for those who have good HBsAg response in the early stage of treatment but no significant decrease in HBsAg level in the follow-up treatment.