In the natural history of chronic hepatitis B, clearance of HBsAg is very rare, with spontaneous clearance of HBsAg reported to be only 0.12%-2.38% and 0.54%-1.98% per year in Asian and Western countries, respectively, and is associated with factors such as age, ALT level, the presence of cirrhosis, HBeAg status, HBV DNA level and HBV genotype. Covalent closed circular DNA (cccDNA) is the transcriptional template of HBV and the reservoir of intrahepatic HBV, whereas HBsAg is the replication product of HBV cccDNA, and its level reflects the transcriptional activity of cccDNA; therefore, the main challenge of anti-HBV therapy is to remove intrahepatic cccDNA, and the therapeutic goal is to achieve HBsAg clearance. Although nucleos[t]ide analogues (NA), the current first-line drugs for the treatment of hepatitis B, can potently inhibit HBV replication, the HBsAg clearance rate is extremely low.