In the treatment of chronic hepatitis B, immune control is the key, and current domestic and international guidelines emphasize the importance of HBeAg seroconversion and HBsAg clearance as therapeutic goals. PEG-IFNα has both immunomodulatory and viral suppressive effects, and produces a sustained response effect after a fixed course of treatment, resulting in a high rate of HBeAg seroconversion and a decrease in the quantitative level of HBsAg, with gradual acquisition of HBsAg clearance. PEG-IFNα is suitable for both HBeAg-positive and HBeAg-negative patients, and its HBsAg clearance effect does not differ between genotypes. In the future, it is expected that individualized treatment with PEG-IFNα by monitoring quantitative HBsAg levels during treatment will bring more patients with chronic hepatitis B infinitely closer to clinical cure of hepatitis B. Archimedes once told the world, “Give me a fulcrum and I can pry up the earth. At one time, the burden of chronic hepatitis B was also so overwhelming for countries around the world, especially in the Asia-Pacific region, such as China. 1966~1971, Professor Robert M. Friedman discovered the antiviral mechanism of IFN, and in 1976, Greenberg et al. first reported the treatment of chronic active hepatitis B with human leukocyte IFN, and since then, IFN has been on the stage of chronic viral Since then, IFN has entered the stage of chronic viral hepatitis treatment. Today, with the continuous improvement of theoretical knowledge and accumulation of evidence-based data on the application of PEG-IFN in chronic hepatitis B, more and more patients are showing a near-cure response with the disappearance of HBsAg. We hope that by further improving the treatment protocol of PEG-IFN, we can say to patients with slow hepatitis B in the future, give us a chance to use PEG-IFN, and we will return your hope of cure. HBV DNA conversion, HBeAg seroconversion and HBsAg clearance – from viral suppression to immune control When everyone’s understanding of hepatitis treatment still remained on regression of yellowing and enzyme reduction, the discovery of inhibiting viral replication and delaying the progression of cirrhosis and hepatocellular carcinoma undoubtedly produced a huge shock to people’s perceptions, and sustained and significant suppression of HBV DNA levels gradually became the recommended therapeutic target (endpoint) in various guidelines or expert consensus. With the introduction of more potent nucleoside (acid) analogues, HBV DNA conversion is no longer a luxury for many patients; it means significant suppression of the virus. Although data from long-term, large-sample studies of these drugs need to be further refined, past studies with lamivudine did show that sustained suppression of viral replication can slow the progression of disease to liver cancer. Unfortunately, relying on nucleoside (acid) analogs to maintain HBV DNA levels below detectable levels does not solve all problems. The antiviral mechanism of nucleoside (acid) analogs is to act directly on the HBV polymerase, inhibiting only the replication of the virus – this is one of the reasons why nucleoside (acid) analogs are prone to relapse after discontinuation, thus requiring long-term use, which makes the resistance and safety issues of nucleoside (acid) analogs particularly salient. The special replication intermediate, covalently closed circular DNA (cccDNA), which exists during HBV replication, provides a stable template for viral replication, and data show that it takes about 14.5 years for nucleoside (acid) analogs alone to exhaust the replication template of the virus without drug resistance. It is clear that viral clearance is almost impossible with nucleoside analogs alone to inhibit viral replication. In addition, it has been documented that in patients with persistently negative or maintained low levels of DNA, some patients still have progressive intrahepatic lesions. This is because it is the host’s immune response that is central to the control of HBV infection, and the interaction between the body’s immune system and the virus determines the prognosis of HBV infection. Liver damage occurs primarily as a result of the body’s immune system’s failed attempts to clear the virus. The progression of chronic hepatitis B disease and the complete clearance of HBV ultimately depend on the body’s immune response, suggesting that simply using HBV DNA conversion as a treatment endpoint is clearly insufficient and that we need other indicators that truly reflect the control of the virus by the body’s immune system. The immune response is a response against antigens, and the level of HBV-related antigens can reflect the immune status of the body. For example, HBeAg is consistently considered an immunogen and is closely related to the severity of the disease, such that the incidence of HCC is significantly higher in patients who are positive for both HBsAg and HBeAg than in those who are positive for HBsAg alone. Studies have shown that HBeAg seroconversion, either spontaneously or after antiviral therapy, can reduce the risk of liver failure and improve survival. Achieving HBeAg seroconversion is a marker of immune control of chronic hepatitis B. Ninety-five percent of patients achieve long-term remission, with a significantly reduced chance of cirrhosis and hepatocellular carcinoma, and some patients have the opportunity to achieve HBsAg clearance (Figure 1). Therefore, HBeAg clearance and seroconversion are recognized as another therapeutic endpoint for HBeAg-positive patients, and thus become an important indicator for determining the effectiveness of antiviral therapy. For HBeAg-negative patients, after AASLD (2007) proposed HBsAg clearance as a treatment endpoint, EASL also included HBsAg clearance as an “ideal endpoint” for treatment of chronic hepatitis B (regardless of HBeAg status) in its 2009 guidelines (Table 1). This is because long-term follow-up studies have shown that patients who achieve HBsAg clearance have a much higher survival rate than those who do not (Figure 2). Data from a 10-year follow-up of 11,893 patients in Taiwan showed that HBeAg seroconversion reduced the incidence of HCC by 10-fold; whereas HBsAg seroconversion reduced the incidence of HCC by up to 60-fold. In addition, HBsAg quantitative testing methods have been improved in recent years, and many researchers have conducted quantitative monitoring of HBsAg levels at various stages of disease and treatment, and found that the levels and dynamics of HBsAg correlate well with the levels and magnitude of changes in cccDNA, reflecting the levels of intrahepatic cccDNA and intrahepatic HBV DNA, which is more sensitive, specific and realistic than HBV DNA. It is a more sensitive, specific and realistic “hepatitis B progress barometer” than HBV DNA. If patients are given effective treatment before they develop liver cancer or decompensated cirrhosis, those who clear HBsAg will have a good long-term prognosis, and thus HBsAg clearance and seroconversion are considered the closest indicators of clinical cure. If the treatment endpoints of antiviral therapy for chronic hepatitis B are compared to medals in the Olympic Games, then HBV DNA conversion can only be considered a bronze medal, while gold and silver medals are attributed to HBsAg clearance and HBeAg clearance and seroconversion, respectively. In order to obtain clinical cure, the clearance of HBsAg is not achieved overnight but through a ladder of steps like climbing Mount Everest: first, the decline of HBV DNA and the decline of HBeAg and HBsAg antigen levels; subsequently, the achievement of HBeAg seroconversion and HBV DNA conversion; then, the clearance of HBsAg through immune control to achieve clinical cure; and finally, the reduction of liver cancer and The incidence of liver cancer and cirrhosis is reduced and the survival period is prolonged. Among them, obtaining HBeAg seroconversion is an important marker for the emergence of immune control and a precondition for obtaining HBsAg clearance. PEG-IFN therapy significantly improves HBeAg seroconversion and HBsAg clearance The clearance of viruses depends on the body’s immune response against HBV, and IFN has incomparable advantages over nucleoside (acid) analogs in this regard. The multiple mechanisms of action allow IFN to produce a sustained follow-up response after a fixed duration of treatment, obtaining a high rate of HBeAg seroconversion and the possibility of HBsAg clearance. Several follow-up studies of 10 years or more have demonstrated that IFN treatment of chronic hepatitis significantly reduces the incidence of cirrhosis and hepatocellular carcinoma compared to untreated controls. For example, a Meta-analysis showed that IFN reduced the incidence of hepatocellular carcinoma by 34% compared to placebo. The advent of PEG-IFNα is a major breakthrough in the antiviral treatment of IFN, which has led to a significant increase in the convenience of IFN use and patient compliance and tolerability, as well as a significant improvement in the efficacy of IFN. Clinical studies have shown HBeAg seroconversion rates as high as 42% after 48 weeks of treatment with PEG-IFNα-2a (Pyroxine, PEGASYS) and 1 year of discontinuation (Figure 3). Marcellin et al. treated HBeAg-negative patients with piroxin ± lamivudine (LVD) with a 5-year follow-up showed that virologic and biochemical responses were maintained at the end of the piroxin treatment course with or without the combination of LVD, and more importantly, HBsAg clearance increased yearly after the end of treatment, from 4.8% at 1 year after the end of treatment to 12.2% at 5 years (Figure 3). The rate of HBsAg clearance increased from 4.8% at 1 year after the end of treatment to 12.2% at 5 years (Figure 4). The annual HBsAg clearance rate in these patients was 12.8%, which is much higher than the natural clearance rate of HBsAg. More encouragingly, HBsAg clearance was similar across genotypes, which is certainly a boon to patients previously considered refractory. Another advantage of PEG-IFNα is that drug resistance does not occur, regardless of the patient’s previous therapy. One study reported that PEGASYS achieved the same follow-up response and HBsAg clearance in patients who had failed prior treatment with nucleoside (acid) analogs (lamivudine, emtricitabine, and adefovir) as in primary care patients. The above data strongly suggest that IFN-based therapy helps hosts control and clear chronic hepatitis B infection. Enhancing the host immune response with PEG-IFNα induces HBeAg and HBsAg serologic conversion, allowing control of chronic hepatitis B to progress toward a cure. Quantitative detection of HBsAg to guide individualized treatment with PEG-IFN In this APASL meeting, Prof. Marcellin and Prof. Jiajie Liao also reported on the predictive value of quantitative detection of HBsAg levels during PEGASYS treatment for post-treatment response in HBeAg-positive and HBeAg-negative chronic hepatitis B patients, respectively. For HBeAg-positive slow hepatitis B, at 24 weeks of treatment with PEGASYS, 35% of patients had HBsAg <1500 IU/mL, of whom 50% achieved HBeAg seroconversion at the study endpoint, and 18% of these patients achieved HBsAg clearance. For HBeAg-negative patients, it was also found that among those who achieved HBsAg clearance, the degree of HBsAg decline during treatment was significantly greater than in non-responders. These findings suggest that the quantitative level of HBsAg can be measured during treatment to predict the response effect at the end of treatment and thus help clinicians make decisions to optimize the treatment regimen for PEGASYS. For example, one study showed that for patients with persistent decreases in HBeAg and HBsAg quantification, continued extension of the regimen significantly improved HBeAg clearance, with HBeAg clearance of 53% and cumulative HBsAg clearance of 27% at 96 weeks of treatment with PEGASYS. Conclusion: Immune control is the key to the treatment of chronic hepatitis B. Current guidelines at home and abroad emphasize the importance of HBeAg seroconversion and HBsAg clearance as therapeutic goals. PEG-IFNα is suitable for both HBeAg-positive and HBeAg-negative patients, and its HBsAg clearance effect does not differ between genotypes. In the future, it is expected that the individualized treatment with PEG-IFNα by monitoring the quantitative level of HBsAg during the treatment process will bring more patients with chronic hepatitis B infinitely closer to clinical cure of hepatitis B.