In 1963, Dr. Blumberg discovered a novel antigen, named Australia antigen (AuAg), in a blood sample from Australia by protein electrophoresis, and later confirmed that this AuAg was associated with hepatitis B (HB) and in fact belonged to the surface antigen of hepatitis B virus (HBV). It was later confirmed that this AuAg was associated with hepatitis B (HB) and in fact belonged to the surface antigen of hepatitis B virus (HBV), thus opening a new era of hepatitis B research. It was for this important discovery that Dr. Blumberg was awarded the Nobel Prize in Medicine and Physiology in 1976. Over the next 50 years, many important discoveries and advances were made in the field of hepatitis B research, including the application of a range of diagnostic techniques. the emergence of hybridoma technology and molecular cloning in the 1980s contributed to the continuous advancement of hepatitis B pathogenesis research. Recombinant hepatitis B vaccines expressed in yeast cells have played an important role in the preventive control of HBV infection in highly endemic areas. At the same time, clinicians’ research on the natural history of hepatitis B patients has become a model for clinical disease research in the medical community. Regarding the clinical treatment research of hepatitis B, Chinese herbal medicine played a very important historical role before the clinical antiviral treatment in the 20th century. Ancestral medicine has a long historical understanding of liver disease, has accumulated a wealth of experience, and has an important clinical position in the treatment of liver disease. A series of hepatoprotective, enzyme-lowering, anti-inflammatory, anti-fibrotic, and even anti-viral and anti-tumor drugs developed from ancestral medicine played a very important function in a specific historical stage, and some treatments and therapeutic drugs still play an important role in the treatment of clinical liver diseases until now. Until the mid-1980s, recombinant human interferon alpha (IFN-α) played a historic role as an immunomodulatory and antiviral agent introduced into the treatment of chronic hepatitis B (CHB). Subsequently, in order to improve the biological characteristics of IFN-α, which has too short a half-life in the blood, pegylated interferon (Peg-IFN), which was chemically modified by applying in vitro polyethylene glycol, achieved better efficacy. The mechanism of interferon class for CHB is complex, with direct antiviral and CHB treatment through immunomodulatory mechanisms, characterized by serological conversion of HBeAg in about 30% of HBeAg positive patients after one year of treatment and six months of discontinuation. 1989 saw the introduction of lamivudine (LAM), an oral antiviral therapy targeting the nucleoside analogue of HBV polymerase/reverse transcriptase In 1989, LAM, an oral antiviral drug targeting HBV polymerase/reverse transcriptase, was marketed, turning a new page in the study of antiviral therapy for CHB. Since then, adefovir (ADV), telbivudine (LdT), entecavir (ETV), and tenofovir (TDF) have emerged for the HBV polymerase therapeutic site, and some countries and regions have approved oral nucleos(t)ideanalogues such as clivudine (CLV) and emtricitabine (ETC). NUCs] antiviral therapeutic agents, thus starting a new era of oral antiviral therapy in clinical practice. NUCs for CHB are characterized by convenient oral administration, rapid and obvious effect of inhibiting HBVDNA replication, and antiviral therapy can slow down disease progression in CHB patients at different stages, reduce the occurrence of liver cirrhosis (LC) and hepatocellular carcinoma (HCC), and reduce complications, prolong survival and improve quality of life in patients with end-stage liver disease. Therefore, it remains the main treatment for CHB patients at present. However, the mechanism of action and action characteristics of NUCs determine the limitations of their application in the antiviral therapy of CHB. nucs mainly inhibit the reverse transcription link from HBV RNA to HBV DNA, while there is no direct inhibition and clearance of the so-called HBV cccDNA in the nucleus of hepatocytes, therefore, the effect of this treatment has obvious limitations, requiring long-term treatment, discontinuation of drugs after Relapse, long-term use of some drugs to develop drug resistance, drug therapy can not completely block disease progression, can not eliminate the occurrence of HCC, and long-term treatment generates a huge economic burden. Therefore, regarding the antiviral treatment of CHB, it must also be designed from a completely new strategy, and treatment strategies and therapeutic drugs aimed at clearing the virus from the body will be the main development direction of CHB treatment research. From the molecular biological characteristics of the life cycle of HBV and the process of antiviral therapy development, there are prospects for development from several angles of entry to eradicate HBV infection. Through decades of efforts, the development of anti-human immunodeficiency virus (HIV) therapeutic drugs has made great progress. In recent years, considerable progress has also been made in the development of drugs against hepatitis C virus (HCV), allowing the use of all-oral drugs that can cure more than 95% of patients with chronic hepatitis C (CHC) in a course of as short as 8 weeks. Therefore, major international antiviral therapeutic drug development companies have devoted their major R&D efforts to the development of new anti-HBV drugs. It can be expected that in 3-5 years, a large number of anti-HBV therapeutic drugs with different mechanisms and targets of action will be available, and it can be predicted that antiviral therapy for CHB will also usher in a new therapeutic strategy and therapeutic drugs for the all-oral clearance of HBV from the liver. From the results of HBV life cycle studies, HBV cccDNA in the nucleus of hepatocytes is undoubtedly an important therapeutic target. It has been projected that HBV cccDNA in the nucleus of hepatocytes has a long half-life of up to 14.3 years in the absence of external intervention. In fact, this result is a mathematical model extrapolation under the condition of continuous depletion and replenishment of HBV ccc DNA without intervention. In fact, if the source of HBV ccc DNA replenishment in the liver is blocked and the degradation of HBV ccc DNA is accelerated, it is entirely possible for HBV cccDNA to be controlled in the short term. Without careful analysis of this result, there is a lack of confidence in the development of new drugs targeting this segment. HBV ccc DNA is a combination of HBcAg, HBVRNA, HBV DNAP, and histone (histone) of the host cell, which entwine to form a minichromosome, during which the N-terminus of the HBcAg protein mediates homo The binding, wrapping, and reverse transcription of HBV RNA and the subsequent methylation modification of HBVDNA, acetylation modification of histone, and binding of chaperone protein molecules are all related to the formation and transcriptional activity of HBV ccc DNA. formation and transcriptional activity. Regarding the development of therapeutic drugs targeting HBV ccc DNA as a focus, Cai et al. reported that CCC-0975 and CCC-0346 could reduce the synthesis of HBV ccc DNA. the binding of HBcAg and daughter HBVDNA into nuclear particles with the cytoplasmic terminal portion of unglycosylated modified HBsAg macroprotein is an important link in the formation of viral particles, after which The glycosylation modification of HBsAg is related to the assembly of viral particles, therefore, glycosylase (glucosidase) inhibitors of HBsAg glycosylation modification also have a good prospect for development. In addition, for the mechanism of HBV infection of hepatocytes, NTCP and Myrcludex-B exhibit a link to block HBV infection of hepatocytes. the binding and wrapping of HBcAg protein with pregenomic HBV RNA is an important link in the formation of nuclear particles. Studies have shown that Heteroaryldihydropyrimidines can block the binding and wrapping of HBcAg with pregenomic HBV RNA, and its representative drug is Bay41-4109, which can block the formation of viral nucleoshell and become another hot spot in the development of therapeutic drugs. Regarding the secretion of HBsAg, a series of novel triazolopyrimidine inhibitors, which can effectively inhibit the secretion of HBsAg, are able to inhibit the release of HBV particles. The nucleic acid polymer currently under development, amphipathicoligonucleoside, or Rep 9AC’ can block the process of HBsAg secretion. Viruses are simple organisms that have to complete their life cycle with the help of some components of the host cell. Therefore, breakthroughs in the development of new anti-HBV drugs can also be achieved by targeting the components of host cells that are indispensable for HBV replication. For example, TLR7 and TLR9 have a very important role in activating pDC in vivo, therefore, the development of agonists (agonist) targeting TLR7 is progressing rapidly. For example, GS-9620 is already in the process of phase I clinical study [18]. For the characteristics of immunity to HBV infection, IL-7 and IL-21 are also promising for R&D. PD-1/PDL-1 molecules are of great importance in immunity to HBV infection, so it is also important to explore the development of anti-HBV therapeutic effects of PD-1/PDL-1 blockers. Research on therapeutic protein and nucleic acid vaccines against Tregs has also progressed. There have also been some encouraging research advances in the development of biotechnologies such as RNAi technology for HBV [20], RNA editing technology for APOBEC3G, and CRISPR/Cas9 for HBV. Although it is still difficult to predict very clearly what exactly the future strategies and drugs for anti-HBV therapy will be based on the latest advances in the development of new drugs against viruses and hosts, one thing is very clear, namely, that in the near future, clinical drug development for anti-HBV therapy will soon enter a new era of all-orally administered, virus-clearing therapy. At present, our strategy is to continue to apply hepatitis B vaccine to protect the susceptible population and use accessible anti-HBV drugs to maximize the inhibition of HBV replication and reduce disease progression; at the same time, we should also strengthen basic research on the molecular biology of HBV life cycle to find new targets and new therapeutic drugs to make our due contribution to the ultimate cure of CHB. HIV and HCV The golden era of new drug development has passed, and it is the right time to develop new drugs for HBV. We firmly believe that a new era of antiviral therapy for CHB patients is coming!