Disease progression in chronic hepatitis B threatens the life and health of patients, and antiviral therapy needs to be given aggressively to improve disease progression and reduce the risk of cirrhosis and liver cancer. There are three internationally recognized endpoints for the treatment of chronic hepatitis B: reduction of HBV virus to below detectable levels during treatment is an unsatisfactory endpoint, and continued treatment is required to obtain this response, with a high relapse rate once the drug is discontinued; durable HBeAg serologic conversion after drug discontinuation is a satisfactory treatment endpoint, and achieving this treatment endpoint makes it possible to achieve no relapse after drug discontinuation; and durable HBsAg clearance after drug discontinuation is the ideal treatment Endpoint. Among the above three treatment endpoints, HBsAg clearance, i.e. clinical cure, maximizes the risk of cirrhosis and hepatocellular carcinoma and is considered to be the best treatment scenario, close to “cure”. The data show that the incidence of liver cancer is 0.1%, <0.1% and 0.02% when the above three treatment endpoints are achieved, respectively. Among the current antiviral drugs, long-acting interferon has both antiviral and immunomodulatory effects and achieves high HBeAg serological conversion and HBsAg clearance, i.e., an advantage in terms of clinical cure. The data show that nucleoside analogs have low HBeAg serological conversion and HBsAg clearance rates with long-term treatment, especially the HBsAg clearance rate is about 1%, which is close to the natural clearance rate without treatment. In contrast, pegylated interferon alpha-2a treatment of HBeAg-positive patients with chronic hepatitis B, also known as major triplets, showed a HBeAg serological conversion rate of more than 61% at 24 weeks after discontinuation of the drug. Once HBeAg serological conversion is obtained with long-acting interferon therapy, the efficacy will be more durable. Patients with HBeAg serological conversion at 24 weeks after drug discontinuation can have a durable response rate of 86% 1 year after drug discontinuation, and such patients can have a HBsAg clearance rate of 30% 3 years after drug discontinuation. So can all patients with major triple yang achieve such efficacy, or achieve better efficacy, with pegylated interferon alpha-2a therapy? To obtain good results, you first need to master the right timing of treatment. The so-called major triple-positive refers to three positive indicators of HBsAg, HBeAg anti-HBc. In fact, a significant proportion of these patients are asymptomatic hepatitis B virus carriers, who are in a state of immune tolerance. The clinical manifestations are that although HBeAg is positive and HBV DNA levels are high (often >107 copies/ml), transaminase levels are normal and there are no significant abnormalities in liver histology or only mild inflammation. This means that the HBV virus and human immunity coexist peacefully, causing no liver damage, and the existing antiviral drugs are ineffective, and antiviral therapy is generally not done. The immune tolerance period can be maintained for several years or even decades. During this stage, one should insist on monitoring follow-up to keep track of one’s condition. If elevated serum transaminases are found, it means that this peaceful coexistence is broken and the immune clearance phase is entered, and the autoimmune function starts to play the role of immune clearance, and at this time, if one receives antiviral treatment, an internal and external response will be able to achieve twice the effect with half the effort. Obviously, the immune clearance phase is the right time for treatment with pegylated interferon alpha-2a. In particular, patients in the immune clearance phase with strong immune function, i.e. low HBV DNA level (less than 10 copies/ml) and high ALT level (more than 5-10 times the upper limit of normal value) are advantageous patients for pegylated interferon alpha-2a, which have better treatment efficacy and higher chance of achieving clinical cure. Secondly, adjusting the treatment regimen to the patient’s response during treatment can also lead to better outcomes. Studies have confirmed that changes in HBsAg quantification during pegylated interferon alpha-2a treatment predict HBeAg serological conversion after drug discontinuation. The more HBsAg decreases at 24 weeks of treatment, the higher the rate of future HBeAg serologic conversion. So how many patients fall into this lucky category? The results of the study show that more than 80% of patients with HBsAg quantification below 20,000 IU/ml at 24 weeks of treatment, nearly half of them will show HBeAg seroconversion six months after the end of treatment. What should be done for patients who do not fall into this response category? Regular testing of HBsAg quantification before as well as during treatment, and giving different treatment regimens based on changes in HBsAg quantification can improve outcomes. The treatment regimen recommended by experts is as follows: patients with HBsAg ≤ 1500 IU/ml at 24 weeks of treatment are expected to have the best efficacy, and generally Pyroxin can achieve good results with 48 weeks of treatment; those with HBsAg 1500-20000 IU/ml at 24 weeks will need to be treated up to 72 weeks to achieve better efficacy; a small number of patients with HBsAg ≥ 20000 IU/mL at 24 weeks and A small number of patients with HBsAg ≥ 20,000 IU/mL at 24 weeks and HBV DNA ≥ 5.0 lgcopies/ml are more difficult to achieve good outcomes and may be considered for combination nucleoside (acid) analogue therapy. In conclusion, pegylated interferon α-2a is the treatment of choice for patients with major triplets to achieve clinical cure, and the latest NICE guideline clearly states that it should be used as the first-line treatment option for the primary treatment of patients with chronic hepatitis B, with nucleoside analogues being the second-line treatment for treatment failure or intolerance. Clinical application of pegylated interferon alpha-2a with good timing and adjustment of the treatment regimen according to response during treatment can improve efficacy and increase the chances of achieving clinical cure.