Natural history and pathogenesis
Natural history
The natural history of HBV infection depends on the interaction between the virus and host. One of the most important factors influencing chronicity is the age at HBV infection. The risk of chronicity is 90% in neonates and infants under 1 year of age23 and <5% in adults.24
According to virological, biochemical, and histological characteristics, the natural history of chronic HBV infection is generally divided into four phases:25,26 HBeAg-positive chronic HBV infection (formerly known as the immune tolerance phase, chronic HBV carrier status), HBeAg-positive CHB (formerly known as the immune clearance phase, immune active phase status), HBeAg-negative chronic HBV infection (formerly known as the immune control phase, inactive HBsAg carrier status), and HBeAg-negative CHB (formerly known as the reactivation phase) (Table 2).
Table 2Phases of chronic HBV infection
| Phases | HBeAg-positive chronic HBV infection (immune tolerance phase, chronic HBV carrier) | HBeAg-positive CHB (immune clearance phase, immune active phase) | HBeAg-negative chronic HBV infection (immune control phase, inactive HBsAg carrier) | HBeAg-negative CHB (reactivation phase) |
|---|
| HBsAg (IU/mL) | >1×104 | + | <1×103 | + |
| HBeAg | + | + | − | − |
| HBV DNA (IU/mL) | >2×107 | + | − | + |
| ALT | <ULN | Elevated (Persistently or repeatedly) | <ULN | Elevated (Persistently or repeatedly) |
| Liver histology | None/minimal necroinflammation and fibrosis | Obvious necroinflammation and/or fibrosis | Minimal/mild inflammation but different degrees of fibrosis | Obvious necroinflammation and/or fibrosis |
The following three points should be noted: First, although immunology has been formerly used to describe the phases of the natural history of chronic HBV infection, no direct immunological evidence or markers are available. Moreover, defining the phases of all HBV infections using virological, biochemical, and histological markers is difficult. Second, not all patients with HBV infections experience all of the above four phases in sequence. For example, there is no “immune tolerance phase” for most adolescents and adults who are infected with HBV; instead, these patients enter the “immune clearance phase” directly. Third, the phases of chronic HBV infection are not entirely consistent with the clinical diagnosis and indication for initiation of antiviral therapy.
Spontaneous HBeAg seroconversion can occur in HBeAg-positive CHB patients, with an annual incidence of 2–15%. Patients under the age of 40 years with elevated ALT levels, genotype A, or genotype B show a higher incidence of spontaneous HBeAg seroconversion.27 Following HBeAg seroconversion, HBsAg clearance occurs in 0.5–1.0% of patients yearly.1 Notably, in one study, it was found that even 10 years after HBsAg clearance, approximately 17.8% of the patients still tested positive for HBV DNA in their serum.28 Furthermore, patients over 50 years of age or complicated with liver cirrhosis, HCV, or hepatitis D virus (HDV) infection may still develop HCC, even if they have achieved HBsAg seroconversion.29,30
The annual incidence of cirrhosis is 2–10% in CHB patients without antiviral therapy. Risk factors for this include host factors (older age, male sex, age >40 years when the HBeAg seroconversion occurs, and persistently elevated ALT levels), viral factors (HBV DNA >2,000 IU/ml, persistently HBeAg positive, and genotype C), co-infection with HCV, HDV, or HIV, and concomitant risk factors for liver injury (e.g., alcohol or obesity).31,32 Notably, the annual incidence of progression from compensated to decompensated cirrhosis is 3–5%, and the 5-year survival rate of decompensated cirrhosis is 14–35%.31
The annual incidence of HCC ranges from 0.2% to 1.0% in non-cirrhotic patients with HBV infection31–33 and from 3% to 6% in patients with cirrhosis. The risk factors include age >40 years, male sex, liver cirrhosis, family history of HCC, high levels of HBV DNA, alcohol consumption, smoking, diabetes mellitus, obesity, and exposure to aflatoxin.31,34,35
For some treatment-naïve patients with a 1-year follow-up, it can be challenging to classify them into the above four phases according to their HBV DNA levels, ALT levels, and liver histology. In the literature, these patients are considered to be in the “indeterminate phase.” According to the four phases defined previously, the proportion of those in the “indeterminate phase” is as high as 28–55%.36–38 In the so-called “indeterminate phase,” patients are not in an independent stage, but rather the stage itself is difficult to determine. Generally, it is difficult to distinguish HBeAg-positive chronic HBV infection from HBeAg-positive CHB and HBeAg-negative chronic HBV infection from HBeAg-negative CHB. It is noted that “indeterminate phase” patients have a higher risk of disease progression compared to true HBeAg-positive chronic HBV (formerly known as the immune tolerance phase) or HBeAg-negative chronic HBV (formerly known as inactive HBsAg carrier status) patients, and antiviral therapy might be required.36 With the introduction of the updated guideline in 2022, which provides a clearer classification of the natural history, the proportion of individuals in the “indeterminate phase” is expected to significantly decrease. This development is favorable for expanding the population eligible for antiviral therapy.
Pathogenesis
The pathogenesis of chronic HBV infection is complex and has not yet been fully elucidated. Evidence suggests that HBV cannot directly kill hepatocytes, and the immune response to the virus is the main pathogenesis for hepatocyte injury and necroinflammation. Persistent or repeated necroinflammation is an important factor in the progression of chronic HBV infection to liver cirrhosis and HCC.
The non-specific (innate) immune response plays an important role in the early stages of HBV infection and induces the subsequent specific (adaptive) immune response.39,40 HBV can suppress the intensity of non-specific immune responses through HBeAg- and HBx-mediated interference with various signal transduction pathways. Patients with CHB often show a low frequency of myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) in the peripheral blood, with impaired mDC maturation and reduced interferon α produced by pDC. Consequently, patients show a reduced capacity to directly clear viruses and induce HBV-specific T lymphocytes, negatively affecting virus clearance.41
HBV-specific immune responses play an important role in HBV clearance.42 CD8+ cytotoxic T lymphocytes can induce apoptosis of virus-infected hepatocytes and secrete interferon-γ to suppress the expression and replication of HBV genes in hepatocytes.43 During chronic infection, HBV-specific T lymphocytes are prone to apoptosis, with significantly reduced ability to secrete cytokines and proliferate, resulting in exhausted function, which may be one of the mechanisms leading to persistent HBV infection.44 Currently, the lack and/or functional insufficiency of HBsAg-specific cytotoxic T lymphocytes is considered a significant contributing factor to immune tolerance in patients with chronic HBV infection.45
Clinical diagnosis
Chronic HBV carrier
Patients in this phase are young patients with high HBV DNA levels (usually >2×107 IU/mL), high serum HBsAg levels (usually >1×104 IU/mL), and positive HBeAg. Additionally, serum ALT and AST levels are persistently normal (as determined through three consecutive follow-up visits within one year, each with an interval of at least three months) in these carriers. Furthermore, liver histopathological examinations reveal no obvious necroinflammation or fibrosis in these patients.
HBeAg-positive CHB
Patients in this phase include those that are serum HBsAg-positive, HBeAg-positive, and HBV DNA-positive. Additionally, they can be accompanied by persistent or repeated abnormal ALT levels, can present with obvious necroinflammation by liver histopathology, or present with significant fibrosis (≥F2), as indicated by liver histopathology or non-invasive markers.
Inactive HBsAg carriers
Patients in this phase include those that are serum HBsAg positive, HBeAg negative, anti-HBe positive, and HBV DNA negative (undetectable). Additionally, they typically have HBsAg levels <1,000 IU/ml and persistently normal ALT and AST levels (as determined through three consecutive follow-up visits within one year, each with an interval of at least three months). Furthermore, in these carriers, liver cirrhosis tends to be absent, and inflammation tends to be mild.
HBeAg-negative CHB
Patients in this phase include those that are serum HBsAg positive, persistently HBeAg negative, often anti-HBe positive, and HBV DNA positive. Additionally, these patients are accompanied by persistent or repeatedly abnormal ALT levels or obvious necroinflammation when analyzed using liver histopathology or demonstrate significant fibrosis (≥F2) as indicated by liver histopathology or non-invasive markers.
Occult HBV infection (OBI)
OBI patients exhibit specific characteristics. They test negative for serum HBsAg, indicating the absence of detectable surface antigens. However, they may still have detectable HBV DNA in their serum and/or liver tissue. Among individuals with OBI, approximately 80% show positive results for serum antibodies such as anti-HBs, anti-HBe, and/or anti-HBc, which is referred to as seropositive OBI. On the other hand, approximately 1–20% of OBI cases show negative results for all serological markers, known as seronegative OBI.
HBV-related liver cirrhosis
The diagnosis of HBV-related liver cirrhosis should meet the following criteria: (1) and (2) (pathological diagnosis), or (1) and (3) (clinical diagnosis).
The patient is currently HBsAg positive, or HBsAg negative and anti-HBc positive with a clear history of chronic HBV infection (with a history of being HBsAg positive for >6 months), with other etiologies being ruled out.
Liver pathology reveals cirrhosis.
Two or more of the following five items are met, excluding those with non-cirrhotic portal hypertension:
Imaging studies show signs of cirrhosis and/or portal hypertension;
Endoscopy reveals gastroesophageal varices;
LSMs indicate cirrhosis (ALT<ULN, LSM ≥12.0 kPa, ULN<ALT<5× ULN, and LSM ≥17.0 kPa);76
Blood biochemistry reveals decreased albumin levels (<35 g/L) and/or prolonged PT (>3 seconds longer than controls).
Complete blood count reveals platelet counts <100×109/L, after excluding other etiologies.
Clinically, cirrhosis is classified into compensated and decompensated stages according to the presence of severe complications such as ascites, gastroesophageal variceal hemorrhage, and hepatic encephalopathy. Patients with compensated cirrhosis have liver function reserve Child-Pugh class A. Decompensated cirrhosis is defined as the development of severe complications such as ascites, gastroesophageal variceal hemorrhage, or hepatic encephalopathy in patients with cirrhosis;92 these patients have liver function classified as Child-Pugh class B or C.
Re-compensation
Some patients with decompensated HBV-related cirrhosis have the potential to revert to compensated cirrhosis following antiviral therapy, a phenomenon referred to as “re-compensation” of cirrhosis. This is defined as the absence of severe complications such as ascites, hepatic encephalopathy, and gastroesophageal variceal hemorrhage for at least one year and improved liver function after removing or controlling the underlying etiologies.1,93 Chinese scholars recently conducted a 120-week follow-up of HBV-related decompensated cirrhosis and proposed that MELD scores <10 and/or Child-Pugh class A status (albumin >35 g/L, INR <1.5 and total bilirubin <34 µmol/L) can be used as the criteria for stable improvement of liver function in patients with re-compensation.94
Indications of antiviral therapy
The indications for antiviral therapy are generally based on serum HBV DNA (a high-sensitivity assay is recommended), ALT levels, and the severity of the liver disease in combination with factors such as age, family history, and concomitant diseases. These factors are assessed comprehensively to determine the risk of disease progression (Fig. 1).96
The ALT threshold for initiating antiviral therapy has traditionally been based on the folds of the ULN. However, several studies have demonstrated that even in patients with ALT levels below the ULN, there is a correlation between ALT levels and significant necroinflammation (≥G2) or fibrosis (≥F2) on liver pathology.97,98 Moreover, elevated ALT levels have been associated with the development of decompensated cirrhosis and HCC.99,100 It is important to note that the recommended ALT cutoff values for initiating treatment vary among international guidelines, and consensus has been difficult to achieve due to differences in factors such as race, research population characteristics, control methods of factors that can affect ALT levels (such as alcohol consumption, body weight, and diabetes), study designs (cross-sectional studies or cohort studies), and ALT measurement methods. In the interest of expanding antiviral therapy and improving treatment coverage, this updated guideline recommends lowering the ALT cutoff value for initiating treatment in order to reduce the incidence of liver inflammation, fibrosis, cirrhosis, HCC, and liver disease-related deaths. Notably, many international guidelines have set the ALT cut-off value for treatment as 30 U/L for men and 19 U/L for women.100–102 However, whether this ALT cutoff value applies to Chinese CHB patients requires further investigation.
To mitigate the risk of disease progression, it is essential to strengthen antiviral therapy in patients who are at risk. Notably, a family history of HBV-related cirrhosis or HCC and age >30 years are two independent risk factors for disease progression.9,103–108 Therefore, in patients diagnosed with liver cirrhosis, it is imperative to prioritize and intensify antiviral therapy.
Studies have suggested that even in patients with HBV DNA-negative compensated cirrhosis, the cumulative incidence of HCC in patients not receiving antiviral treatment is significantly higher compared to those receiving antiviral treatment.109 Thus, many international guidelines and consensus statements recommend active antiviral treatment due to the high risk of disease progression in these patients.103,110,111 Furthermore, antiviral therapy could be considered when evidence of compensated or decompensated cirrhosis is present, regardless of ALT levels, HBV DNA levels, or HBeAg status.
Recommendation 10: Antiviral therapy is recommended for patients with detectable HBV DNA and persistently elevated ALT levels (>ULN) after excluding other causes (B1).
Recommendation 11: Antiviral therapy is recommended for patients with detectable HBV DNA, regardless of ALT levels, if one of the following criteria are fulfilled:
Family history of HBV-related cirrhosis or HCC (B1) ;
Age >30 years (B1);
Non-invasive or histological examinations indicate significant inflammation (G≥2) or fibrosis (F≥2) (B1);
HBV-related extrahepatic manifestations (B1).
Recommendation 12: Antiviral therapy is recommended for HBV-related compensated or decompensated cirrhosis, regardless of ALT levels, HBV DNA levels, or HBeAg status. Other causes of cirrhosis (such as alcohol-associated fatty liver disease, metabolic dysfunction-associated fatty liver disease, diabetes, and autoimmune or genetic metabolic liver disease) should be identified and treated (B1).
Interferon alpha treatment
Peg-IFN-α and interferon (IFN)-α have been approved for CHB treatment in China.
The regimen and efficacy of Peg-IFN-α treatment
Peg-IFN-α monotherapy
Peg-IFN-α treatment of treatment-naive CHB patients can achieve partial virological response (<50% in both HBeAg-positive and HBeAg-negative patients) and HBsAg clearance (HBsAg clearance rate of 8.7–11.0% after three years of treatment). HBV DNA <2×108 IU/mL, high levels of ALT (2–10×ULN) or liver inflammation ≥G2, genotype A or B, low HBsAg levels (<25,000 IU/mL),95 and high quantitative levels of anti-HBc antibodies at baseline65 are good predictors of IFN efficacy.
Combination therapy of Peg-IFN-α and NAs
For select eligible CHB patients receiving NAs, the addition of Peg-IFN-α in a combination therapy regimen has been shown to promote a clinical cure.138–142 Patients with low HBsAg levels (<1,500 IU/ml) and negative HBeAg before IFN therapy are more likely to achieve clinical cure after sequential Peg-IFN-α therapy.139–141 Early virological response (HBsAg <200 IU/mL or a >1 log10 IU/mL decrease at 24 weeks of treatment) can help predict clinical cure after 48–96 weeks of combination therapy.95,142,143 Low levels of HBcrAg and high levels of anti-HBs at the end of treatment may predict a durable clinical cure after Peg-IFN-α discontinuation.144
Peg-IFN-α may reduce the incidence of HBV-related HCC
Some studies have shown that Peg-IFN-α treatment reduced the incidence of HCC in CHB patients during long-term follow-up;95,138,145 however, this requires further confirmation.
Adverse events and contraindications of Peg-IFN-α
The main adverse events of Peg-IFN-α include influenza-like syndrome (fever, headache, myalgia, fatigue), bone marrow suppression, and others (autoimmune diseases, mental disorders).9,95
Contraindications to Peg-IFN-α therapy include:
Absolute contraindications: pregnancy or pregnancy planning, history of mental illness (with a history of schizophrenia or severe depression), uncontrolled epilepsy, decompensated cirrhosis, uncontrolled autoimmune diseases, and underlying diseases, such as severe infection, retinal disease, heart failure, and chronic obstructive pulmonary disease.
Relative contraindications: thyroid disease, history of depression, uncontrolled diabetes, high blood pressure, and heart disease.
Recommendation 13: For patients with HBeAg-positive CHB, NAs (ETV, TDF, TAF, or TMF) are recommended (A1). NAs can be discontinued after HBsAg loss has been confirmed. For those patients who prefer to stop the NAs, discontinuation can be attempted if ALT normalization, HBV DNA undetectable, and HBeAg seroconversion are achieved after one year of treatment and maintained during 3 years of consolidation (monitor every 6 months), along with HBsAg <100 IU/mL. Close monitoring is necessary, and a longer duration of consolidation can help reduce the virological relapse rate (B2).
Recommendation 14: Peg-IFN-α can be considered for HBeAg-positive CHB patients. For patients with a decline in HBV DNA <2 log10 IU/mL and an HBsAg level >2×104 IU/mL at treatment week 24, Peg-IFN-α should be stopped and NAs should be initiated (A1). For patients who respond well to Peg-IFN-α, a 48-week treatment duration is preferred, which can be extended but should not exceed 96 weeks (B1).
Recommendation 15: For patients with HBeAg-negative CHB, NAs (ETV, TDF, TAF, or TMF) are recommended (A1). In patients who achieve undetectable HBV DNA and HBsAg loss (with/without anti-HBs) and maintain this response during a six-month consolidation period, NAs can be discontinued. However, follow-up is warranted in these patients (B1).
Recommendation 16: Peg-IFN-α can be considered for HBeAg-negative CHB patients. In patients with a decline in HBV DNA level <2 log10IU/mL or a decline in HBsAg level <1 log10IU/mL after 12 weeks of treatment, Peg-IFN-α should be stopped and NAs should be initiated (B1). For patients who respond well to Peg-IFN-α, a 48-week treatment duration is preferred, which can be extended but should not exceed 96 weeks (B1).
Recommendation 17: Peg-IFN-α as an add-on therapy can be considered in highly selected patients that meet specific criteria, including undetectable HBV DNA, HBeAg seroconversion, and HBsAg levels <1,500 IU/mL after NAs treatment. The decision to pursue a clinical (functional) cure with Peg-IFN-α should take into account the patient’s preference. If the patient’s HBsAg level is <200 IU/mL or decreases to >1 log10 IU/mL after 24 weeks of add-on therapy, adding Peg-IFN-α for 48–96 weeks is recommended. In contrast, if their HBsAg level remains at or above 200 IU/mL after 24 weeks of add-on therapy, discontinuing Peg-IFN-α and continuing NAs treatment is recommended (B2).
Recommendation 18: Long-term antiviral therapy with ETV, TDF, or TAF is recommended for patients with HBV-related compensated cirrhosis. Close monitoring of adverse events is required if Peg-IFN-α is used (A1).
Recommendation 19: Long-term treatment with ETV or TDF is recommended for patients with HBV-related decompensated cirrhosis Peg-IFN-α is contraindicated (A1). TAF can be considered if necessary (B1).
Antiviral therapy recommendations for special populations
Patients with poor response and low viremia
Although potent oral antiviral therapy with low drug resistance can effectively suppress HBV replication, some patients still present with poor response or low viremia. In these cases, suboptimal responses are defined as HBV DNA >2×103 IU/mL, and low viremia (LLV) is defined as detectable HBV DNA <2,000 IU/mL in CHB patients receiving ETV, TDF, TAF, or TMF for at least 48 weeks with good compliance.152 Notably, LLV after antiviral therapy is closely related to the fibrosis progression of CHB, the risk of decompensated cirrhosis and HCC, and reduced long-term survival rates.153–155
Recommendation 20: In CHB patients treated with ETV, TDF, TAF, or TMF for 48 weeks but who still have detectable HBV DNA (>20 IU/mL), after excluding medication non-adherence, NAs can be modified. This can involve switching to or adding on TDF or TAF in those who are already on ETV, and vice versa (B1). The addition of Peg-IFN can also be considered (B1).
Recommendation 21: In patients with HBV-related cirrhosis treated with ETV, TDF, or TAF for 24 weeks but who still have detectable HBV DNA (>20 IU/mL), after excluding medication non-adherence, NAs can be modified. This can involve switching to or adding on TDF or TAF in those who are already on ETV, and vice versa (C2).
Patients undergoing chemotherapy, targeted therapy, and immunosuppressant therapy
HBV reactivation or even liver failure may occur in patients with chronic HBV infection undergoing chemotherapy, targeted therapy, or immunosuppressant therapy. The risk of HBV reactivation in HBsAg-positive patients is 5–8 times that in HBsAg-negative patients.156 Additionally, the risk of HBV reactivation varies among patients with different anti-HBs statuses, with anti-HBs-positive patients experiencing a 5.0% risk and anti-HBs-negative patients facing a higher risk of 14.0%.157 To mitigate these risks, the implementation of prophylactic antiviral therapy has proven to be effective in significantly reducing the incidence of HBV reactivation.158
ETV, TDF, or TAF antiviral therapy is recommended in patients undergoing chemotherapy, targeted therapy, or immunosuppressant therapy.133,159,160 In these patients, the recommendations for antiviral therapy, follow-up monitoring, and drug withdrawal are the same as those for patients with CHB or cirrhosis. For chronic HBV carriers, inactive HBsAg carriers, or patients with negative HBsAg and positive anti-HBc, if NAs are being employed as the current prophylactic antiviral therapy, discontinuation of NAs can be attempted 6–12 months after completing chemotherapy, targeted therapy, or immunosuppressant therapy. For patients receiving B lymphocyte monoclonal antibodies or undergoing hematopoietic stem cell transplantation, discontinuation of NAs can be attempted at least 18 months after treatment. However, it should be noted that NAs discontinuation can lead to HBV relapse or exacerbation. Therefore, it is recommended to closely follow up with patients for a period of 12 months after discontinuation. During this follow-up period, regular monitoring of HBV DNA levels and liver biochemical markers should be conducted at intervals of 1–3 months.161,162
Recommendation 22: For patients with pending chemotherapy, targeted therapy, or immunosuppressive therapy, screening for HBV markers (HBsAg, anti-HBs, and anti-HBc) should be recommended (A1). For HBsAg-and/or HBV DNA-positive patients, NAs (ETV, TDF, or TAF) should be initiated at least one week before starting chemotherapy, targeted therapy, or immunosuppressive therapy, or at the same time if necessary (A1). For HBsAg-negative and anti-HBc-positive patients, ETV, TDF, or TAF antiviral treatment is recommended if they have advanced liver fibrosis/cirrhosis, plan to receive B lymphocyte depletion therapy with monoclonal antibody agents, or undergo hematopoietic stem cell transplantation (B1).
Management of pregnancy-related conditions
It is recommended to screen women of childbearing age and those planning pregnancy for HBsAg. Additionally, women with HBV should be tested for HBsAg-positive DNA.163 The treatment indications for newly diagnosed CHB during pregnancy are the same as those for CHB patients, and TDF antiviral therapy can also be initiated. Pregnant women with CHB who initiate antiviral therapy before or during pregnancy should continue the antiviral therapy until delivery and decide whether to continue the original treatment regimen or switch to other NAs or Peg-IFN-α according to their virological response.
A high serum HBV DNA level is a high-risk factor for mother-to-child transmission. Approximately 85% of HBeAg-positive pregnant women without antiviral therapy present HBV DNA levels >2×105 IU/mL. Therefore, maternal-positive HBeAg can be used as a surrogate indicator for antiviral therapy to prevent mother-to-child transmission when HBV DNA detection is unavailable.164,165
Clinical studies with small samples have shown that the effect of TAF in preventing mother-to-child transmission is similar to that of TDF, and TAF is well-tolerated in pregnant women.166,167 However, the safety profiles of TAF in neonatal birth defects and breastfeeding remain to be further confirmed. In the case of an unintended pregnancy while taking TAF, more evidence is needed to determine whether it is necessary to switch to TDF. However, there is currently no evidence regarding the safety of TMF in fetuses and newborns.
Pregnant women in the immune tolerance period who receive NAs can discontinue the drug immediately or 1–3 months after delivery. It is important to note that hepatitis activity may occur in a significant percentage of patients (17.2–62.0%) after drug withdrawal, with most cases occurring within 24 weeks.168,169 Therefore, postpartum monitoring should be strengthened. To ensure proper assessment, it is recommended to re-test liver biochemical markers and HBV DNA levels 4–6 weeks after delivery. Furthermore, re-detection is recommended every 3 months until 6 months after delivery if the mother’s liver biochemical markers are normal, whereas antiviral treatment is recommended if HBV activity is detected.
Recommendation 23: For HBsAg-positive women that are pregnant or planning for a pregnancy who are indicated for antiviral therapy, TDF is recommended after comprehensive counseling and obtaining informed consent (B1). In addition, TAF can be considered in patients with renal insufficiency (B2).
Recommendation 24: For women with incidental pregnancy and already on antiviral therapy, TDF should be continued while ETV or other NAs should be switched to TDF, without termination of pregnancy (B1). If IFN therapy is already being used, a switch to TDF is recommended if the pregnancy is to be continued after comprehensive counseling and obtaining informed consent (C2).
Recommendation 25: For pregnant women with HBV DNA levels >2×105 IU/mL, TDF therapy should be initiated at week 24–28 of gestation after comprehensive counseling and obtaining informed consent (A1). For mothers with HBeAg-positive chronic HBV infection (immune tolerance phase), TDF may be withdrawn immediately or 1–3 months after delivery. Liver biochemistry and HBV DNA levels should be tested at least every 3 months until 6 months after delivery. In addition, antiviral therapy should be initiated immediately for those with active hepatitis (A2). For mothers with HBeAg-positive or-negative CHB, TDF can be continued postpartum after comprehensive counseling and obtaining informed consent. Breastfeeding is not contraindicated in women undergoing TDF treatment (C2).
Pediatric patients
Antiviral therapy should be initiated immediately in children with active CHB or liver cirrhosis. Children with HBeAg-positive CHB and elevated ALT levels can be treated with a limited course of common IFN-α or Peg-IFN-α-2a to achieve clinical cure (HBsAg clearance with or without anti-HBs).104,170 ETV, TDF, or TAF treatment can also be used. It is important to note that the dosages of ETV, TDF, or TAF should adhere to the recommendations provided by regulatory bodies such as the US Food and Drug Administration, WHO, and relevant drug instructions.109 Additionally, NAs can be administered to children with CHB and cirrhosis who have not achieved HBeAg seroconversion or who are HBeAg-negative after treatment with common IFN-α or Peg-IFN-α-2a.170,171
No consensus has been reached on the need for treatment in children in the immune-tolerance phase. A study found that children in the clinically diagnosed immune tolerance phase presented with a certain degree of inflammatory activity and/or fibrosis through histological examinations.172 Furthermore, studies have indicated a significant increase in the HBV DNA response rate, HBeAg seroconversion rate, and HBsAg clearance rate among children aged 1–7 years in the immune tolerance phase.173,174 However, it is crucial to systematically evaluate treatment decisions for children in the immune tolerance phase, taking into consideration long-term treatment safety and the risk of drug resistance.175,176 This evaluation should include histological examination, non-invasive examination for liver fibrosis, and dynamic liver function evaluation.
Recommendation 26: For children with advanced liver disease or cirrhosis, antiviral therapy should be initiated immediately, regardless of age; however, long-term treatment safety and drug resistance should also be considered. IFN-α is recommended for children aged ≥1 year, ETV or TDF for children aged ≥2 years, Peg-IFN-α-2a for children aged ≥5 years, and TAF for children aged ≥12 years (A1).
Recommendation 27: For children with positive HBV DNA and ALT<ULN, liver biopsy is recommended, and antiviral therapy could be initiated for those with histological grade G≥1 (B1). For children aged 1–7 years, even without a liver biopsy, antiviral treatment can be considered after comprehensive counseling with their guardians and obtaining informed consent (C1).
Patients with renal impairment
High-risk factors for renal impairment include decompensated cirrhosis, uncontrolled hypertension, uncontrolled diabetes, concomitant use of nephrotoxic drugs, or solid organ transplantation.1 When there is a high risk of renal impairment, changes in renal function should be monitored when applying NAs. In addition, serum creatinine and phosphorus levels should be monitored regularly when ADV or TDF is administered.177
ETV or TAF is recommended as the first-line treatment for patients with chronic kidney disease, renal insufficiency, or renal replacement therapy.128,178 In contrast, treatment with ADV or TDF is not recommended. When TAF is applied to patients without HIV infection, there is no need to adjust the dosage of TAF when the estimated glomerular filtration rate (eGFR) is ≥15 mL/min. However, the dosages of other NAs require adjustment when the eGFR is ≤50 mL/min. Please refer to the drug instructions for further details.
ETV or TAF can be used as prophylactic or therapeutic drugs in HBsAg-positive kidney transplant recipients. Kidney transplant recipients should avoid treatment with IFN-α or PEG-IFN-α.
Patients with HBV-related glomerulonephritis can be treated with NAs. As a result, the recommendation is to consider ETV or TAF as suitable treatment options. For patients treated with ADV or TDF who develop renal or bone disease or are at high risk, switching to ETV or TAF is recommended.178
Recommendation 28: For CHB patients with chronic kidney disease, renal insufficiency, or renal replacement therapy, ETV or TAF is recommended, and ADV or TDF treatment should be avoided (B1). For CHB patients with a high risk of renal impairment, renal function should be closely monitored during NAs treatment. Moreover, in ADV- or TDF-treated patients who develop or are at high risk of renal or bone diseases, switching to ETV or TAF is recommended (B1).
Co-infection of HBV and HCV
All HBsAg-positive patients should be tested for anti-HCV, and further detection of HCV RNA levels is required for patients with positive anti-HCV. Patients with positive HCV RNA should be treated with direct-acting agents (DAA), and it should be noted that these patients are at risk of HBV reactivation. Therefore, during anti-HCV therapy and within three months of drug discontinuation, combined antiviral therapy with ETV, TDF, or TAF is recommended with close monitoring.179
HBsAg-negative and anti-HBc-positive patients are also at risk of HBV reactivation during DAA treatment. Therefore, monthly monitoring of serum HBV DNA and HBsAg levels is recommended in these patients. Moreover, antiviral therapy is recommended when HBsAg is positive in these patients.179
Recommendation 29: For HBsAg-positive CHC patients receiving DAA therapy, adding NAs is recommended until 12 weeks after DAA cessation. For HBsAg-negative and anti-HBc-positive CHC patients on DAA therapy, HBV DNA and HBsAg levels should be closely monitored, and NAs treatment is recommended when HBsAg becomes positive (B2).
Co-infection with HBV and HIV
As long as there is no indication to suspend the anti-HIV treatment, anti-retroviral therapy should be initiated as soon as possible, regardless of the level of CD4+T lymphocytes. Patients co-infected with HIV and HBV should be treated with drugs suppressing the two viruses simultaneously, including two drugs with anti-HBV activity, to avoid the development of drug resistance to NAs. For a highly active anti-retroviral therapy (HAART) regimen, TDF, TAF + lamivudine, or emtricitabine (FTC) (mixture formulations of TDF + FTC and TAF + FTC are available) are recommended. In addition, HBV-related markers, such as HBV DNA, liver biochemical markers, and liver imaging markers, should be monitored during treatment. For HIV and HBV co-infected patients, it is not recommended to select a regimen that contains only one NAs that is effective against HBV (TDF, lamivudine, ETV, telbivudine, or ADV) to avoid the development of drug resistance to NAs.180,181
It should be noted that for patients with renal insufficiency:
If the creatinine clearance rate is <60 mL/min, TDF cannot be selected, and the dosage of TDF should be adjusted.
If the creatinine clearance rate falls between 30 mL/min and 50 mL/min, a regimen containing TAF+ (FTC or lamivudine) can be applied. However, it is important to note that TAF has not been approved for use in patients with creatinine clearance rates <30 mL/min.
When TDF/TAF cannot be used, ETV should be added to the HAART regimen. For pregnant women co-infected with HIV and HBV, a regimen containing lamivudine (or FTC) + TDF is recommended.182
Recommendation 30: For HIV-HBV co-infected patients, a regimen against both HIV and HBV (including two drugs for HBV) is recommended (A1).
Patients with HBV-related liver failure
Patients with HBV-related acute, subacute, acute-on-chronic, and chronic liver failure are known to have a high mortality rate. Therefore, antiviral therapy is recommended for patients with HBsAg positivity.
Anti-HBV therapy has been demonstrated to improve the long-term prognosis of HBV-associated ACLF.183,184 Additionally, many clinical studies have shown that ETV, TDF, and TAF can treat HBV-related ACLF.185–187 In particular, TAF offers the advantage of reducing renal toxicity compared to TDF while maintaining antiviral efficacy.128 Furthermore, early and rapid reduction of HBV DNA levels is the key point of treatment in this context, as the survival rate of patients can be improved if the HBV DNA level is reduced by 2log10 IU/mL within 2–4 weeks.184,186,188 Consequently, antiviral therapy should be continued for an extended duration in patients following recovery from liver failure.
Recommendation 31: For HBsAg-positive patients with acute, subacute, acute-on-chronic, or chronic liver failure, NAs (ETV, TDF, or TAF) are recommended (A1).
HBV-related HCC patients
Anti-HBV therapy plays a critical role in the management of HBV DNA-positive HCC patients, as it can effectively reduce HCC recurrence after surgery and improve overall survival.189 Among the available options, NAs (ETV, TDF, or TAF) with rapid and high efficacy are preferred. In patients without contraindications, IFN-α can also be considered as a treatment option.
HBV reactivation may occur in patients with HCC who are HBsAg-positive but HBV-DNA-negative during liver resection, hepatic arterial chemoembolization, radiotherapy, or systemic chemotherapy. In these patients, antiviral therapy using ETV, TDF, or TAF is recommended.
Recommendation 32: For HBsAg-positive patients with HBV-related HCC, NAs (ETV, TDF, or TAF) are recommended (A1).
Liver transplant patients
When patients undergo liver transplantation due to HBV-related diseases (including liver failure and HCC), anti-HBV regimens should be selected appropriately to reduce the risk of HBV re-infection in the transplanted liver. The selection of a specific anti-HBV therapy regimen for HBV-infected patients undergoing transplantation depends on the primary risk factor for re-infection, which is determined by the HBV DNA level prior to transplantation.
Undetectable HBV DNA before transplantation indicates a low risk of re-infection. NAs (ETV, TDF, or TAF) can be applied as early as possible before surgery to prevent HBV reactivation, and HBIG is not needed after surgery.190 If HBV DNA is positive before transplantation, it indicates a high risk of re-infection, and NAs (ETV, TDF, or TAF) can be applied as early as possible before surgery to reduce HBV DNA levels. HBIG should be injected intravenously during the anhepatic period of surgery.
In addition to the long-term application of NAs after surgery, low-dose HBIG should be injected simultaneously for 0.5–1.0 years.191 Notably, a recent study found that shortening the course of HBIG in patients treated with ETV remains effective.192 However, close monitoring of HBV DNA is required to detect drug resistance and promptly adjust the treatment regimen when patients have already been administered other NAs. In addition, some studies reported that hepatitis B vaccination after liver transplantation could prevent recurrence; however, its clinical application remains controversial.190
Recommendation 33: For HBsAg-positive patients undergoing liver transplantation for HBV-related disease, antiviral therapy with ETV, TDF, or TAF should be initiated before surgery (A1).