Hepatitis B virus (HBV) infection remains a major health threat worldwide, with more than 350 million people living with chronic hepatitis B (CHB) worldwide and more than 600,000 people dying each year from liver failure, cirrhosis and hepatocellular liver cancer (HCC) caused by HBV infection. Although the hepatitis B vaccine has been used for more than 30 years and acute HBV infection has decreased significantly, the number of people with chronic HBV infection is still quite large. China has about 93 million people with chronic HBV infection, including about 20 million cases of CHB. How to “cure” hepatitis B is a problem that has plagued people for many years. At this stage, antiviral therapy for CHB mainly includes two major classes of drugs, namely long-acting interferon (PEG-IFN, immunostimulatory therapy), and nucleoside (acid) analogs (NA, direct viral suppression). In recent years, with the popular use of powerful NA (e.g., entecavir, tenofovir), effective and durable inhibition of HBV DNA replication is not difficult, however, the clearance rate of HBsAg in patients during NA treatment is very low (0-3% after 1 year of drug use), and virological relapse often occurs after NA discontinuation, and NA often requires long-term or even lifelong application. Unlike NA, the rate of HBsAg disappearance and HBsAg serological conversion in CHB patients treated with PEG-IFN antiviral therapy is higher than that of NA, reaching 3-7% after 1 year of discontinuation, and the rate can continue to rise after discontinuation, reaching 8% after 3 years of follow-up. However, adverse drug reactions and pharmacoeconomic characteristics limit the use of PEG-IFN. Currently, the “cure” of hepatitis B is considered to be divided into the following four stages: 1. clinical control: HBV DNA is maintained below the lower limit of detection during drug administration and liver function is normal; 2. immune control: antiviral therapy is discontinued for 12 months after reaching the discontinuation criteria, HBV DNA is still maintained below the lower limit of detection and liver function is normal; 3. clinical cure: antiviral therapy is discontinued for 12 months after reaching the discontinuation criteria, HBV DNA is still maintained below the lower limit of detection and liver function is normal; 3. 3, clinical cure: antiviral therapy to achieve HBsAg clearance or serological conversion; 4, complete cure: complete clearance of HBV cccDNA from the body of the infected person. Most of the existing clinical CHB treatment regimens can only achieve clinical cure, even so, the existing clinical cure rate of CHB is still low. The 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B recommend that clinical cure of CHB, i.e., sustained virologic response after cessation of therapy, disappearance of HBsAg with ALT reversion and improvement of liver histology, should be pursued as much as possible for partially suitable patients. The treatment endpoints for CHB are also defined: 1. Desirable endpoints: HBeAg-positive and HBeAg-negative patients who obtain durable HBsAg disappearance with or without HBsAg serologic conversion after discontinuation of therapy. 2.Satisfactory endpoints: HBeAg-positive patients, obtaining sustained virological response and ALT normalization with HBeAg serological conversion after drug discontinuation; HBeAg-negative patients, obtaining sustained virological response and ALT normalization after drug discontinuation. 3. The basic endpoint: if sustained response after drug discontinuation cannot be obtained, virological response (undetectable HBV DNA) is maintained for a long time during antiviral therapy. In recent years, in order to achieve a “cure” for CHB, there have been a number of basic research and clinical cure studies on new targets for HBV replication cycle, the following are the preliminary results of representative studies. It is well known that cIAP can prevent the body from clearing HBV-infected cells by blocking the TNF-mediated process of killing or clearing infected cells. It was found that Birinapant, an analog of cystatin protease activator (Smac), antagonizes cIAP in a mouse model by mimicking the function of endogenous Smac, thereby facilitating the clearance of HBV-infected cells by the body. It was also found that the application of Birinapant up to week 4 not only rapidly reduced HBV DNA to the lower limit of detection, but also reduced HBsAg to non-detectable and even serological conversion of HBsAg. Compared with monotherapy, Birinapant in combination with ETV cleared HBV DNA more rapidly and was well tolerated by animals. These studies suggest that Birinapant and other Smac analogues have potential as new drugs for CHB treatment and can be used in combination with existing anti-hepatitis B virus drugs to enhance their efficacy. Lymphotoxin β (LTβ) receptor agonists Existing studies have shown that the persistence of HBV cccDNA in hepatocytes is a major cause of viral relapse and that cccDNA has the ability to infect hepatocytes even during antiviral therapy. Therefore, the presence of cccDNA as a template for viral replication is a major cause of persistent HBV infection and relapse after discontinuation of existing antiviral drugs. Clearance of cccDNA can be an indicator of a complete cure for chronic hepatitis B. Finding new therapeutic regimens that target cccDNA may be the best way to completely clear HBV. Lymphotoxin β is a secreted protein produced by lymphocytes after activation by stimuli such as antigen or mitogen and in the case of certain tumors and autoimmune diseases. ltβR initiates intracellular signal transduction pathway after binding to LTβ. by activating LTβR, Lucifora et al. not only inhibited the release of HBsAg, HBeAg, HBV DNA, but also promoted intracellular cccDNA degradation and complete clearance of virus in vivo. At the cellular level, LTβR activator BS1 reduced cccDNA by 90% in HBV-infected dHepaRG cells; in HBV-infected human primary hepatocytes (PHH), activation of LTβR not only reduced HBV DNA and promoted HBeAg serological conversion, but also effectively reduced cccDNA by 95%. Compared with lamivudine (LAM), LTβR agonists had longer-lasting antiviral effects with no rebound after drug discontinuation. At the animal level, LTβR agonistic antibody ACH6 reduced HBV DNA, HBcAg, etc. in HBV transgenic mice. the mechanism of cccDNA clearance by LTβR agonists has been largely elucidated, and activation of LTβR promotes the expression of APOBEC3, which binds cccDNA to promote its degradation. No apoptosis or transaminase elevation was observed by activation of LTβR in either in vivo or in vitro experiments, suggesting that LTβR clears cccDNA in a specific, non-cytotoxic manner and that LTβR agonist treatment of CHB does not cause massive apoptosis or cell death. III. Dendritic cells (DC)-based immune cell therapy It has been demonstrated that DCs are dysplastic or functionally abnormal in CHB patients, which will eventually cause immune tolerance or deficiency of HBV antigen-specific T cells. Akbar et al. selected 5 patients with CHB and applied HBsAg-sensitized DC cells for 24 weeks, and 2 patients achieved HBsAg negative conversion. A multicenter clinical study of hepatitis B vaccine-sensitized DC combined with interferon/nucleoside analogs for the treatment of chronic hepatitis B is currently underway in China, with significant preliminary efficacy. IV. Combination or sequential treatment with PEG-IFN and NA The combination or sequential PEG-IFN regimen after using NA to reduce viral load has certain advantages over NA alone in terms of HBeAg serological conversion and HBsAg reduction. A multicenter, randomized, open study (OSST study) suggested that patients with HBeAg-positive CHB treated with ETV monotherapy for 9 to 36 months and achieving HBV DNA <1000 copies/mL and HBeAg <100 PEIU/mL had higher HBeAg serologic conversion and HBsAg decline with sequential PEG-IFN for 48 weeks than patients who continued with ETV monotherapy. There was a higher rate of HBeAg serological conversion (14.9% vs. 6.1%) and HBsAg clearance (8.5% vs. 0) than patients who continued on ETV monotherapy. Another study (NEW SWITCH study) suggested that HBeAg-positive patients who achieved HBV DNA <200 IU/mL and HBeAg conversion after 1 to 3 years of NA therapy and then received PEG-IFN sequential therapy for 48 weeks had HBsAg clearance and conversion rates of 16.2% and 12.5%, respectively. Rational optimization of antiviral drug regimens provides a direction for clinical cure of CHB. Therefore, CHB cure is not impossible and more and more CHB patients can be cured with the gradual progress of research. In summary, the goal of CHB treatment is to maximize long-term inhibition of HBV replication, reduce hepatocellular inflammatory necrosis and hepatic fibrosis, delay and reduce the occurrence of liver failure, cirrhotic decompensation, HCC and other complications, thus improving quality of life and prolonging survival time. The current problems for complete cure of CHB include the improvement of cccDNA testing technology, in-depth research on immune control of hepatitis B and the continuous development of new drugs. Although there are many obstacles to a cure for hepatitis B, the pursuit of immune control and clinical cure is more beneficial to the long-term prognosis of patients, and optimization of existing antiviral drug regimens and immune cell therapy in combination with antiviral therapy may become the future direction of curing hepatitis B.