Antiviral treatment is an effective therapeutic strategy for CHB patients that efficiently suppresses HBV replication, decreases inflammatory necrosis in the liver, reduces the incidence of liver cirrhosis and related complications, and reduces the fatality rate associated with hepatocellular carcinoma (HCC) and other liver diseases. In the 2019 China guidelines (Chinese Society of Infectious Diseases, 2019), HBV infection is divided into four phases: immune tolerance, immune clearance, immune control, and immune reactivity, and it is different from the 2015 version (Hou and Lai, 2015; Table 1). Additionally, the 2019 China guidelines eased the restrictions on indications for antiviral therapy, and reducing the demand for HBV-DNA load. Conversely, the HBV-DNA load is considered for the performance of antiviral therapy in the 2018 guidelines (Terrault et al., 2018) updated by the 2018 AASLD guideline and the 2017 EASL guidelines (Table 2). For the treatment of HBV infection with normal ALT (alanine aminotransferase), antiviral therapy is recommended in patients > 30-years-old with a family history of liver cirrhosis or cancer in the 2019 China guidelines. In another case >30-years-old without a family history of liver cirrhosis or cancer, a hepatic biopsy was recommended. Although we can refer to many guidelines, there are many patients failed to fulfill the criteria for treatment at follow-up and eventually developed liver fibrosis, cirrhosis, and cancer (Wang et al., 2013; Alam et al., 2014).

Hepatitis B virus infection is a dynamic process characterized by fluctuations in alanine ALT, which might hint toward immune-mediated virus clearance (Ghany et al., 2020). Since the ALT level is not always indicative of inflammation in the liver, patients with normal ALT levels can present inflammation and fibrosis on liver biopsy. Thus, ALT is used as a substitute for liver inflammation when liver histology is a failure (Wu et al., 2019, 2020; Fang et al., 2022). But the challenge in defining the ULN (upper limits of normal) of ALT is the difficulty of including totally healthy subjects without liver diseases, especially MAFLD (Metabolic-Associated Fatty Liver Disease), the leading cause of liver disease worldwide (Tampi et al., 2020). An Italy study reveals that Male sex, body mass index, glucose, lipids, ferritin, hypertension, and younger age are independent predictors of ALT (Valenti et al., 2021). Many hepatologists call for the adjustment of the ULN of ALT (Park et al., 2008; Chen et al., 2010). In 2019 China guidelines, the ULN remains constant at 50 U/L in males and 40 U/L in females; however, many studies have recommended rational values as 35 U/L in males and 23 U/L in females (Harbour and Miller, 2001; Zheng et al., 2012; Shang et al., 2013). In 2018 AASLD guidelines, the ALT ULN is modified as 35 U/L in males and 25 U/L in females, as described previously (Lee et al., 2010; Ruhl and Everhart, 2012; Terrault et al., 2018). In 2017 EASL guidelines and 2015 APASL guidelines, the ALT ULN is 40 U/L in both males and females (Ruhl and Everhart, 2012; Sarin et al., 2016; European Association for the Study of the Liver, 2017). Therefore, whether patients have normal ALT levels partially depends on the ULN. The ULN values mentioned in this study are consistent with those in the literature.

Patients infected with HBV but have normal ALT levels may exhibit manifestations of liver fibrosis and inflammation upon histological examination (Chang et al., 2021; Liu et al., 2022). Previous studies have shown that people with normal ALT levels develop moderate liver tissue inflammation (16.8–40%) and moderate liver fibrosis (24.2–35.9%) (Ormeci et al., 2016; Tan et al., 2017; Choi et al., 2019; Liu et al., 2022), which are associated with a high risk of progression to liver cirrhosis and cancer. In a retrospective study consisting of 327 HBV DNA + CHB patients who underwent liver biopsy, significant differences were detected between high-normal ALT (20 U/L < ALT < ULN) and low-normal ALT (ALT ≤ 20 U/L) groups in liver inflammation and fibrosis (P < 0.01). The rate of significant liver tissue inflammation is 44.6 and 26.5% corresponding to 20 U/L < ALT < ULN and ALT ≤ 20 U/L, respectively (Duan et al., 2021). Another study (Choi et al., 2019) demonstrated that patients with normal ALT have a significantly decreased risk of long-term liver cancer and required liver transplantation after antiviral treatment compared to those without treatment. Therefore, in cases with normal ALT levels, a comprehensive examination is essential, especially in the condition of liver fibrosis and inflammation, to provide antiviral treatment in a time-dependent manner.

Immune tolerance is a status presenting HBeAg+, high viral replication, and normal ALT. It was put forward as a lack of specific immune response to HBV due to the immature immune system during infancy. No treatment is recommended for such cases in the current guidelines, as it is speculated that patients in the immune tolerance phase have a low risk of progression to liver cirrhosis or cancer (Cornberg et al., 2019; Lee et al., 2020). Moreover, ineffective treatment may lead to a low e-antigen seroconversion rate (Wu et al., 2010; Jeng and Lok, 2021). Patients with immune tolerance are mostly teenagers and readily develop drug resistance because of poor compliance after long-term antiviral treatment (Dolman et al., 2018).

Definitions of IT-CHB differ among guidelines. In 2018 AASLD guidelines, IT-CHB is defined by HBV DNA > 10⁶ IU/mL and normal ALT, while in 2017 and 2019 China guidelines, IT-CHB is defined by HBV DNA > 10⁷ IU/mL and normal ALT. However, the ULN of ALT remains controversial with limited value in distinguishing patients experiencing immune tolerance, as the patients are still at risk of liver inflammation or fibrosis when their ALT levels are defined as normal under the lowest ULN standard (Ormeci et al., 2016; Tan et al., 2017; Choi et al., 2019; Chang et al., 2021; Duan et al., 2021; Liu et al., 2022). Hong et al. (2015) speculated that innate immune cell maturation and helper T lymphocyte development existed before intrauterine exposure to HBV during infancy, while another study discovered HBV-specific T lymphocytes in that period (Bertoletti and Ferrari, 2016). Presumably, the immune tolerance phase refers to a status of mild immune response that is difficult to be recognized, and thus, an accurate diagnosis was challenging. A previous study also found the presence of HBV-DNA integration into the host chromosome and the clonal expansion of stem cells in cases of IT-CHB (Mason et al., 2016). A high level of HBV replication is regarded as an independent risk factor for disease progression to cirrhosis and HCC. Additionally, some experts speculated that liver cirrhosis or cancer progresses dynamically and continuously (Kennedy et al., 2017; Sun et al., 2018). Given the fact that the age of CHB onset is mainly after 30 years, the disease progresses for many years before the onset. Furthermore, there is a decreased transmission in immunotolerant patients bearing a high viral load after antiviral treatment. In all guidelines, no treatment is recommended for immunotolerant patients; instead, antiviral therapy is clarified as alleviating liver tissue inflammation and fibrosis and delaying and decreasing the risk of cirrhosis, relevant complications, and cancer. In patients with IT-CHB, aggressive antiviral treatment is beneficial in lowering the risk of liver cirrhosis and cancer. Whether IT-CHB patient needs treatment requires both individualized and comprehensive assessment implicating multiple factors, such as patient age, willingness to receive treatment, risk of disease progression, virus genotype (Yang et al., 2008; Wong et al., 2013), family history, and lifestyle.

As mentioned above, a family history of HBV-related cirrhosis or HCC is a major factor for treatment. Typically, when people develop cirrhosis or HCC, treatment should be positive, which has been described elsewhere. The following groups are highlighted in this review.

Hepatitis B virus, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) share the same modes of transmission, and hence, superinfection is rather common. HBV coinfected with HCV is likely to progress to cirrhosis, chronic and fulminant hepatitis, and HCC in the liver (Squadrito et al., 2013; Pol et al., 2017). All HBsAg-positive patients should be screened for anti-HCV, especially those at a high risk of infection, such as drug injections and male homosexuality. In coexisting HBV and HCV cases, HBV replication differs from HBV mono-infection and is prevented by IFN (interferon) response from HCV replication compared to direct interactions between viruses (Cheng et al., 2020; Shih and Liu, 2020). In HBV-HCV superinfection, the presence of HBV infection does not affect HCV replication. Cheng et al. reported that ISG (Interferon-stimulated gene) expression mediated by HCV infection induced HBV suppression; on the contrary, both HBV and HCV viruses showed high levels of replication when ISG expression was blocked. Specifically, CXCL10 may be a marker of significant IFN response in HBV-HCV coinfection and HCV clearance. In clinical practice, CHB patients who are RNA-positive for HCV should be treated with DAA (direct-acting antiviral) plus anti-HBV therapy, according to almost guidelines (Figure 1). Moreover, monitoring serum HBsAg and HBV DNA levels monthly during the process in patients who receive DAA with HBsAg-negative and hepatitis virus core antigen-positive (anti-HBc+) is essential in case of HBV reactivation.

In HIV-HBV coinfection cases, early initiation of ARVT is recommended, irrespective of the CD4 count. According to the 2019 China guidelines, the therapy included two types of anti-HBV drugs to avoid HIV resistance to NAs (Chinese Society of Infectious Diseases, 2019).

While receiving immunosuppressive or cytotoxic therapy, patients with HBsAg-positive, anti-HBc-positive or HBsAg-negative, and anti-HBc-positive have the possibility of HBV reactivation. Thus, it is necessary to screen for HBsAg before therapy. In the case of HBsAg-positive, patients should receive anti-HBV prophylaxis before immunosuppression or cytotoxic therapy or consecutively. If HBsAg-negative, HBcAb+ patients undergoing anti-CD20 antibody therapy (for example, rituximab) or stem cell transplantation, should accept anti-HBV prophylaxis for at least 18 months (12 months suggested in 2018 AASLD) after immunosuppressive therapy, as the rate of HBV reactivation is high, according to 2019 Chinese guidelines.

Screening for HBsAg in childbearing age women planning a pregnancy and pregnant women is strongly recommended. When they fulfill the treatment criteria, antiviral prophylaxis with tenofovir disoproxil fumarate (TDF) is a preferred agent. NAs used for the prevention of HBV perinatal transmission in a pregnant woman at weeks 24–28 of gestation with normal ALT but positive HBeAg and high levels of viremia (HBVDNA > 2 × 10⁵ IU/mL) can be stopped immediately or within 3 months after delivery under timely monitoring (Chinese Society of Infectious Diseases, 2019; Kumar et al., 2022).

Solid organ transplant recipients are susceptible to HBV. Donor and recipient HBV infection status and perioperative management are the main determinants of susceptibility. Antiviral therapy and HBIG might reduce reactivation or reinfection after transplantation (Chinese Society of Organ Transplantation and Chinese Medical Association, 2019).

Vaccination against HBV among young Chinese individuals decreased the HBV infection rate. In recent years, several studies reported gradually increasing the horizontal transmission of HBV in early childhood, and family members may be the main source of infection. Interferons and NAs are the potential treatment options according to the age of young people (Pan et al., 2020).