Immunopathological mechanisms of chronic hepatitis B. Studies have shown that low intrinsic and adaptive host immune responses to HBV are important causes of chronic hepatitis B virus infection. The host response to the virus depends on a complex interaction of many immune cell systems, including cells of the innate immune system, dendritic cells (DCs) of the virus-specific T-cell system that play a critical role in presentation, and T cells of the adaptive immune system. In the early stages of HBV infection, the host response is nonspecific and the innate immunity is important, acting through natural killer (NK) cells, interferon alpha, cytokines [mediated by Toll-like receptors (TLR)], and complement. In the late phase of the innate immune response, HBV infection activates adaptive immunity, including cellular and humoral immunity, i.e. CD4+ cell activation and differentiation into Th1 or Th2 phenotypes, with the former primarily regulating the cellular immune response and the latter playing a key role in viral clearance. cd8+ induces rapid proliferation of cytotoxic T cells (CTL) and the antiviral molecules interferon gamma (IFNγ), CD8+ can cause rapid proliferation of cytotoxic T cells (CTL) and production of antiviral molecules interferon γ (IFNγ), TNFα and perforin, thereby clearing infected hepatitis B virus in a cytolytic and non-cytolytic manner. There are three main ways in which the body’s immune system clears infected HBV from the body. (1) The secretion of cytokines such as IFNγ and TNFα is relied on to remove HBV from hepatocytes in a non-cell contact, remote, non-cell lysis manner, and the hepatocytes are not destroyed and the structure and function of normal hepatocytes can be restored. However, strangely, the same clearance of HBV cannot be achieved by using in vitro recombinant cytokines such as IFNγ and TNFα. Therefore, the roles and mechanisms of endogenous and exogenous IFNγ and TNFα cytokines are different, but what exactly the causes and mechanisms are are is not very clear. ②The mechanism relying on apoptosis, that is, adaptive immunity of CTL through its Fas ligand (FasL) and the binding of Fas receptors on the membrane of HBV-infected hepatocytes, induces apoptosis in HBV-infected hepatocytes, and HBV dies with the hepatocytes, thus clearing HBV infection. ③ Through HBV-specific CTL via perforin, the membrane of HBV-infected hepatocytes is perforated, and then effector substances such as granzyme are injected to directly cause the lysis of HBV-infected hepatocytes, also using the mechanism of HBV dying with hepatocytes to clear HBV infection. The main mechanisms leading to persistent HBV infection are low or abnormal intrinsic and adaptive immune responses, such as low intrinsic immune function, low adaptive immune function, and poor antibody affinity. (3) low TLR2 expression by peripheral monocytes; (4) biased differentiation of CD4+ cells into Th2 CD4+ T cell phenotype; (5) reduced synthesis of cytokines such as IFNγ and TNFα; and (6) reduced number and function of HBV-specific CD8+ T cells. Immune-based treatment strategies are key to achieving durable responses and improving long-term prognosis: Many clinical data have shown that HBV infection is closely related to the body’s immunity, including different outcomes in people with different immune status after HBV infection, that suppression of the body’s immune system can lead to activation of latent HBV infection and replication, and that secondary immunity can clear the infected HBV from the body. Meanwhile, studies on the intrinsic and adaptive immunity of chronically HBV-infected patients have found that HBV infection develops because of deficiencies in the body’s intrinsic and adaptive immunity against HBV. Therefore, the clinical application of interferon alpha as a representative immunomodulator to help the body to improve or restore the intrinsic and adaptive immunity against HBV is very important, which is the main reason why some clinical experts believe that immunotherapy is very important. Interferon alpha, which has been used in the treatment of chronic hepatitis B since the early 1990s, is a cytokine with immunomodulatory, antiproliferative, and antiviral properties. Several studies have shown that interferon therapy is effective in increasing the rate of HBeAg seroconversion and reducing the risk of cirrhosis and HCC, especially in patients treated with interferon alpha who achieved seroconversion. Lin et al. conducted a comparative study of 233 HBeAg-positive chronic hepatitis B patients treated with interferon alpha and 233 well-matched untreated HBeAg-positive controls in Taiwan, China. After a 15-year follow-up, the researchers found that the cumulative HBeAg serological conversion rate was 74.6% in the interferon α-treated group, significantly higher than that of 51.7% in the untreated group (P=0.031); the cumulative incidence of cirrhosis was 17.8% in the interferon α-treated group, significantly lower than that of 33.7% in the control group (P=0.041); the cumulative incidence of HCC in the interferon α-treated group The cumulative incidence of HCC in the interferon α-treated group was 2.7%, which was significantly lower than that of the control group, which was 12.5% (P=0.011). The investigators concluded that this result further supports the use of interferon alpha as a first-line treatment for chronic hepatitis B with a fixed course and long-term efficacy. The combination of pegylated interferon with interferon alpha further prolongs the half-life of interferon alpha in the circulation, thus maintaining a stable and effective blood concentration. The efficacy of pegylated interferon alpha-2a in the treatment of HBeAg-positive patients with chronic hepatitis B was evaluated in a large, multicenter, randomized controlled clinical trial. The majority of patients enrolled in the study were Asian, with 87% of Asian patients in the pegylated interferon alpha-2a monotherapy or combination lamivudine group and 85% of Asian patients in the lamivudine monotherapy group. The results showed that the HBeAg serological conversion rate of patients in the pegylated interferon α-2a monotherapy group was 32% at 24 weeks after discontinuation, which was significantly higher than that of 19% in the lamivudine monotherapy group, and HBsAg serological conversion occurred in 3% of patients in the pegylated interferon α-2a monotherapy or combined lamivudine treatment group, compared with 0 in the lamivudine monotherapy group, and combined lamivudine The combination of lamivudine with pegylated interferon alpha-2a did not further improve the efficacy of pegylated interferon alpha-2a. Follow-up to 48 weeks after discontinuation of the pegylated interferon alpha-2a monotherapy group showed that some patients entering the study continued to show delayed response, with an overall HBeAg seroconversion rate of 40%. Similar results were seen in patients with HBeAg-negative CHB, and a large, multicenter, randomized controlled clinical trial by Marcellin et al. evaluated the efficacy of pegylated interferon alpha-2a in the treatment of patients with HBeAg-negative CHB. The results showed that patients treated with piroxin ± lamivudine for 48 weeks had a negative HBsAg regression rate of 8% at 3 years of follow-up, compared with 0 in the lamivudine group. In 2005, Hui et al. presented the results of a study at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), suggesting that pegylated interferon alpha-2a treatment resulted in a significant increase in TLR, CD4+ and CD4+ and CD8+ T-cell activities were significantly increased in patients with HBsAg loss after pegylated interferon alpha-2a treatment. These findings suggest that a fixed course of pegylated interferon therapy can improve immune function in patients with chronic hepatitis B. It can help to increase the durable response rate (HBeAg seroconversion and even HBsAg seroconversion in some patients) and improve the long-term prognosis of patients. In addition to interferon alpha and pegylated interferon, nucleoside (acid) analogs are also widely used in the treatment of chronic hepatitis B because they are convenient for oral administration, have a strong HBVDNA inhibitory effect, and are well tolerated. However, these drugs do not have immunomodulatory activity and have a low rate of HBeAg and HBsAg serological conversion after treatment, making it difficult for most patients to achieve a durable response. A long-term follow-up of lamivudine by Liaw et al. showed that although long-term maintenance treatment with lamivudine slowed disease progression, YMDD mutations led to a significantly higher risk of disease progression, up to 13% at 36 months of follow-up, compared with 5% in wild strains. The rate of resistance to nucleoside analogs also increased with each year of treatment, with a 5-year resistance rate of 63% for lamivudine and 29% for adefovir. Also, studies have shown that nucleoside analogue therapy rarely achieves serological conversion to HBsAg. Outlook: With the introduction of several new antiviral drugs, the treatment strategy for chronic hepatitis B has changed dramatically over the past two decades, and clinical outcomes have improved as a result. Nevertheless, the main challenge for clinicians is to achieve durable control of HBV in more patients with chronic hepatitis B and to reduce the risk of liver disease complications such as cirrhosis and hepatocellular carcinoma. The main differences between current treatment regimens are the durable response after drug discontinuation (interferon alpha) and the maintenance response [e.g., nucleoside (acid) analogs]. Studies suggest that the use of immune-based regimens, such as pegylated interferon, can achieve durable responses in about 1/3 of patients. On the other hand, although nucleoside analogue therapy is well tolerated, it has no clear indication for discontinuation, its duration is difficult to determine, most patients require long-term therapy, and there is a risk of mutation and drug resistance. Therefore, immune-based regimens should be the first-line treatment option for patients. Of course, age, co-morbidities, tolerability and other factors should be taken into account when deciding on a specific treatment regimen. Long-term maintenance therapy with nucleoside analogs may be considered for patients who do not respond to interferon alpha therapy and cannot tolerate it, for patients with advanced cirrhosis, for patients with immune deficiency, and for women with high viral load during pregnancy.