The hard endpoint (clinical endpoint) of CHB therapy is the prevention of cirrhosis, end-stage liver disease, and HCC, but CHB therapy is a long-term process, and surrogate indicators are needed to evaluate the efficacy in therapy and to predict the clinical outcome of patients. The commonly used surrogate indicators are serum HBV DNA load, hepatitis B antigen and antibody, and biochemical and histological changes. HBV clearance is the most critical issue in anti-HBV therapy, but currently applied antiviral drugs are unable to completely remove cccDNA from hepatocytes, and it remains unclear whether NAs can induce a sustained treatment response after drug discontinuation. Some data suggest that NAs treatment can at least partially repair the acquired immune response and that HBsAg clearance can be obtained after NAs treatment with a good prognosis. However, this effect is only temporary and NAs therapy has a weaker role in persistent host immunomodulation compared to IFN. Some recent guidelines differ as to whether NAs can be discontinued in patients with HBeAg-positive CHB and HBeAg-negative CHB. For HBeAg-positive CHB patients, European and American guidelines recommend discontinuing NAs after obtaining HBeAg serologic conversion and continuing consolidation therapy for 6-12 months, while Chinese guidelines recommend continuing consolidation therapy for at least 12 months. However, compared with PegIFN, the durability of HBeAg seroconversion after discontinuation of NAs is poor, therefore, even for patients who have achieved HBeAg seroconversion, HBV DNA should be continuously controlled at low levels. It has been shown that HBsAg clearance/HBsAg seroconversion is associated with sustained disease remission and improved long-term outcomes, suggesting that HBsAg clearance/HBsAg seroconversion is the ideal endpoint for CHB treatment. Throughout the natural history of hepatitis B, most patients with spontaneous HBsAg clearance (0.1-1%) have near-normal liver function and liver histology, HBV DNA below the minimum detection limit, and a significantly reduced risk of HCC; therefore, achieving HBsAg clearance or serologic conversion is the best indication for discontinuation in HBeAg-positive CHB patients treated with NAs. In patients with HBeAg-negative CHB, the relapse rate at one year after discontinuation of NAs is as high as 90%. Treatment response has improved with extended therapy, but 50% of patients still have a virologic relapse one year after discontinuation. Relapses can be exacerbated and cirrhotic failure can occur; therefore, HBsAg clearance/HBsAg serologic conversion is also an optimal indication for discontinuation of NAs therapy in patients with HBeAg-negative CHB. However, only a small number of patients with NAs achieved HBsAg clearance, and the rate of HBsAg clearance in HBeAg-positive CHB patients was only 0% -0. 3% at 1 year of NAs treatment; a meta-analysis showed that it took 52.2 years to completely clear HBSAg in patients treated with NAs. In conclusion, there is still a long way to go to completely control CHB. To achieve a cure for CHB, more novel and effective drugs need to be developed, especially effective viral inhibitors and immunomodulators (e.g., specific activation of antiviral immune response, immune cell therapy, negatively regulated immunomodulatory therapy, etc.). New therapeutic strategies such as the combination of potent antiviral drugs and immunomodulators will be an important direction for future clinical research.