A Chinese expert panel led by the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology developed the first edition of the guidelines for the prevention and treatment of chronic hepatitis B (CHB) in 2005, which were updated in 2010 and 2015, respectively. Over the past 4 years, significant progress has been made in basic and clinical research on chronic infection with the hepatitis B virus (HBV), both at home and abroad. The guidelines were updated again to standardize the prevention, diagnosis, and treatment of CHB and help to meet the goal to eliminate viral hepatitis as a major public health threat by 2030 that was proposed by the World Health Organization (WHO) in 2016.
The present guidelines aim to help clinicians make informed decisions for the prevention, diagnosis, and treatment of CHB; however, they are not intended to be mandatory standards and will probably not cover and solve all the issues associated with the diagnosis and treatment of CHB. Therefore, clinicians should use the best clinical evidence and their expertise, experience, and available medical resources to develop a comprehensive and reasonable diagnosis and treatment plan that addresses individual needs.
The quality of evidence in this guideline is divided into three levels: A, B, and C, and the strength of the recommendations is categorized into two levels, 1 and 2, as given in Table 1. (revised according to the Grades of Recommendation, Assessment, Development, and Evaluation classification system).
Natural history and pathogenesis
Natural history
The natural history of HBV infection depends mainly on the interaction between the virus and the host. The age when HBV infection is acquired is one of the most critical factors that determine whether the HBV infection will become chronic. The risk of chronic HBV infection in newborns and infants aged <1 year is 90%.24 Most people with HBV infection in China are infected during the perinatal period or infancy. The world has achieved significant success in blocking HBV mother-to-child transmission.25 A universal immunization program that combines hepatitis B vaccine and HBIG has been adopted for newborns of HBsAg-positive mothers in China; however, approximately 5–7% of newborns are still infected with HBV due to mother-to-child transmission. This occurs in 7–11% of HBeAg-positive pregnant women and 0–1% in HBeAg-negative pregnant women.26,27
In general, the natural history of chronic HBV infection is divided into four phases based on its natural progression,28–30 namely the immune tolerance phase (chronic HBV carrier state), immune clearance phase (HBeAg-positive CHB), immune control phase (inactive HBsAg carrier state), and reactivation phase (HBeAg-negative CHB) (Table 2). For more details, refer to section IX, “Clinical Diagnosis”. Not all patients with chronic HBV infection will experience all four phases. Patients who are infected with HBV during adolescence and adulthood usually experience no immune tolerance phase and directly enter the immune clearance phase.
Table 2Stages of chronic HBV infection
Markers
| Immune tolerance phase (chronic HBV carrier status)
| Immune clearance phase (HBeAg-positive CHB)
| Immune control phase (inactive HBsAg carrier status)
| Reactivation phase (HBeAg-negative CHB)
|
|---|
| HBV serological markers |
|---|
| HBsAg (IU/mL) | >1×104 | + | <1×103 | + |
| anti-HBs | − | − | − | − |
| HBeAg | + | + | − | +/− |
| anti-HBe | − | − | + | +/− |
| anti-HBc | + | + | + | + |
| HBV DNA (IU/mL) | >2×107 | >2×104 | <2×103 | ≥2×103 |
| ALT | Normal | Persistent or recurrent increase | Normal | Persistent or recurrent increase |
| Liver pathology | No obvious necroinflammation or fibrosis | Obvious necroinflammation, or fibrosis, or both | No or mild inflammation, with varying degrees of fibrosis | Obvious necroinflammation, or fibrosis, or both |
Spontaneous HBeAg seroconversion might occur during the immune clearance phase, with an annual incidence of 2–15%. Patients with age <40 years, elevated ALT, HBV genotype A and genotype B had higher incidence.28,31 After HBeAg seroconversion, the HBsAg clearance rate was 0.5–1.0% annually.32 Ten years after HBsAg disappeared, cccDNA was still detectable in the liver of approximately 14% of these patients.33 Patients with either age >50 years, cirrhosis, or concomitant HCV or hepatitis D virus (HDV) infections can still progress to HCC even if HBsAg has disappeared; however, the incidence rate is low.34
The annual incidence of cirrhosis in CHB patients without antiviral therapy is 2–10%,35 and risk factors include host (older age, male, age >40 years when HBeAg seroconversion occurs, and persistently elevated ALT levels36,37), the virus (HBV DNA >2,000 IU/mL), persistently positive HBeAg status,38 genotype C, coinfection with HCV, HDV, or HIV, and other liver injury-inducing factors (e.g., alcohol or obesity).35 The annual incidence of decompensated cirrhosis from compensated cirrhosis is 3–5%, and the 5-year survival rate of the patients with decompensated cirrhosis is 14–35%.35 The annual incidence of HCC in patients with HBV infection without cirrhosis is 0.5–1.0%.35 The annual incidence of HCC in patients with cirrhosis is 3–6%.39–41 Also, cirrhosis, diabetes, immediate relatives with HCC, high serum HBsAg levels, and exposure to aflatoxin are all associated with a high incidence of HCC.35,42–46 Lower HBsAg levels often suggest that hosts have exerted good immune control over HBV replication and infection. Studies have shown that even if HBeAg is negative and HBV DNA levels are low, patients with higher HBsAg levels (≥1,000 IU/mL) are still at a higher risk of HCC, regardless of genotype B or C.45,46
Pathogenesis
The pathogenesis of chronic HBV infection is complicated and is not fully understood. HBV does not directly kill liver cells. The immune response caused by the virus is the main mechanism that leads to liver cell damage and necroinflammation. Persistent or recurrent necroinflammation is an important factor for patients with chronic HBV infection progressing to cirrhosis and even HCC.
The nonspecific (innate) immune response plays an important role in the initial stages of HBV infection and initiates the subsequent specific (adaptive) immune response.47,48 HBV uses its proteins, such as HBeAg and HBx, to interfere with antiviral signaling pathways that involve Toll-like receptors and retinoic acid-inducible gene I-like receptors; therefore, the level of the nonspecific immune response is suppressed. CHB patients often present with decreased frequencies of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) in the peripheral blood. The ability of mDCs to mature and the ability of pDCs to produce IFN-α are significantly impaired, which make it more difficult for the body to eliminate the virus and induce HBV-specific T lymphocytes, which impedes viral elimination.
The HBV-specific immune response plays a leading role in HBV clearance.49 Major histocompatibility complex class I-restricted CD8+ cytotoxic T lymphocytes can induce the apoptosis of infected hepatocytes and can secrete IFN-γ and suppress the expression and replication of HBV genes in liver cells in a noncytolytic fashion.50 During chronic infection, HBV-specific T cells are susceptible to apoptosis. Their ability to produce cytokines and proliferate is significantly impaired, and their functions become exhausted, which might be one of the mechanisms that lead to persistent HBV infection.51 Currently, it is believed that there are large amounts of HBsAg in serum and liver tissue, and the lack, or dysfunction, or both of HBsAg-specific cytotoxic T lymphocytes is an important cause of immune tolerance in patients with chronic HBV infection.52
Imaging diagnosis
The aim of imaging examination in patients with chronic HBV infection is to monitor clinical progression by the identification of signs of cirrhosis and portal hypertension, and to detect and differentiate space-occupying lesions to make an early diagnosis of HCC.93,94
Abdominal US
Abdominal US is the most commonly used liver imaging technique, because it offers a noninvasive, inexpensive, real-time imaging solution that is easy to repeat. US can demonstrate the size, shape, and parenchymal echogenicity of the liver and spleen, and can determine the calibrator and blood flow of the portal, splenic, and hepatic veins. In addition, it can identify the presence and severity of ascites which suggests the presence of cirrhosis and portal hypertension. Regular US surveillance is essential for the identification of early HCC. Contrast-enhanced ultrasonography can be used to better differentiate the nature of space-occupying lesions. The downside of US is that the image quality and results are susceptible to several factors, such as equipment performance, gas in the gastrointestinal tract, and the operator’s skills.
Computerized tomography (CT)
In patients with CHB, CT is mainly used to investigate the imaging changes of the liver to determine the presence of cirrhosis and portal hypertension and identify/differentiate the space-occupying lesions. Contrast-enhanced multiphase CT scanning has a high sensitivity and specificity for the diagnosis of HCC.
Magnetic resonance imaging (MRI)
MRI is a preferred imaging modality for the liver due to its avoidance of radiation exposure. In general, MRI with enhanced multiphase scans and with hepatobiliary-specific contrast agents is outperformed to contrast-enhanced CT in differentiating benign from malignant space-occupying lesions in the liver.
Pathological diagnosis
The aim of liver biopsy in people with chronic HBV infection is to evaluate the degree of necroinflammation and fibrosis, to determine the presence or absence of cirrhosis, to exclude other liver diseases, thereby providing information on the diagnosis, prognosis, and efficacy assessment.
The main pathological features of CHB are portal and periportal necroinflammation and fibrosis. The inflammatory cells infiltrating the portal area are predominantly lymphocytes with a few plasma cells and macrophages. The aggregation of inflammatory cells often destroys the limiting plate and leads to interface hepatitis (previously called piecemeal necrosis). Degeneration, necrosis (e.g., spotted, bridging, and confluent necrosis) and apoptosis of hepatocytes can be seen in the lobules. Ground glass hepatocytes and apoptotic bodies can be formed by apoptotic hepatocytes, which is proportional to inflammation activity. Chronic necroinflammation in the liver can cause the excessive deposition of extracellular matrix, especially collagen, which results in fibrosis that is manifested by varying degrees of portal fibrous expansion and fibrous septum formation. Masson’s trichromatic staining and reticulin staining can help to determine the degree of liver fibrosis and lobular disarray. Then, cirrhosis develops, which is, by definition, the combination of diffuse fibrosis and regenerative nodules (pseudolobules). In addition, immunohistochemical staining for HBsAg and HBcAg as well as in situ hybridization or PCR for HBV DNA or cccDNA in liver tissue can be exploited.
The scoring systems developed by Knodell, Scheuer, Metavir, or Ishak are widely used to grade hepatic necroinflammation and stage fibrosis in persons with chronic HBV infection.95–98 The Laennec system further subclassifies Metavir stage 4 (cirrhosis) into stages 4A, 4B, and 4C, based on the size of the regenerative nodules and the thickness of fibrous septa.99 In addition, Chinese researchers have proposed a histopathological grading and staging system for viral hepatitis B.100 Comparisons of the various grading and staging systems are shown in Tables 3 and 4.
Table 3Comparisons of major grading standards for liver inflammation
| Score | Knodell’s scoring system
| Score | Scheuer’s scoring system
|
|---|
| Periportal inflammation with or without bridging necrosis | Intralobular degeneration and focal necrosis | Portal inflammation | Portal/periportal activity | Intralobular activity |
|---|
| 0 | None | None | None | 0 | None or minimal | None |
| 1 | Mild piecemeal necrosis | Mild (acidophilic bodies, ballooning degeneration or scattered foci, or both of hepatocellular necrosis in <⅓ of lobules or nodules) | Mild (a few inflammatory cells in <⅓ of portal tracts) | 1 | Portal inflammation alone | Inflammation but no necrosis |
| 3 | Moderate piecemeal necrosis (involving <50% of the circumference of most portal tracts) | Moderate (involving ⅓–⅓ of lobules or nodules) | Moderate (increased inflammatory cells in ⅓–⅔ of portal tracts) | 2 | Mild piecemeal necrosis | Focal necrosis or acidophilic bodies |
| 4 | Marked piecemeal necrosis (involving >50% of the circumference of most portal tracts) | Marked (involving >⅔ of lobules or nodules) | Marked (dense inflammatory cells in >⅔ of portal tracts) | 3 | Moderate piecemeal necrosis | Marked focal cell damage |
| 5 | Moderate piecemeal necrosis plus bridging necrosis | – | – | 4 | Marked piecemeal necrosis | Damage includes bridging necrosis |
| 6 | Marked piecemeal necrosis plus bridging necrosis | – | – | | |
| 10 | Multilobular necrosis | – | – | | |
Table 4Comparisons of major staging standards for liver fibrosis
| Knodell’s scoring system | Scheuer’s scoring system | Metavir’s scoring system | Wang Tailing’s scoring system | Ishak’s scoring system |
|---|
| 0 | No fibrosis | 0 | No fibrosis | 0 | No fibrosis | 0 | No fibrosis | 0 | No fibrosis |
| 1 | Fibrous expansion of portal areas | 1 | Fibrous expansion of portal areas | 1 | Fibrous expansion of portal areas, without fibrous septa | 1 | Fibrous expansion of portal areas | 1 | Fibrous expansion of some portal areas, with or without short fibrous septa |
| 2 | – | 2 | Periportal fibrosis or portal-portal fibrous septa but intact architecture | 2 | Fibrous expansion of portal areas, with few fibrous septa | 2 | Periportal fibrosis, with fibrous septa but intact architecture | 2 | Fibrous expansion of most portal areas, with or without short fibrous septa |
| 3 | Marked bridging (portal-portal as well as portal-central) | 3 | Fibrosis with architectural distortion but no obvious cirrhosis | 3 | Numerous septa, with architectural distortion, but no cirrhosis | 3 | Fibrous septa with architectural distortion but no obvious cirrhosis | 3 | Fibrous expansion of most portal areas with occasional portal-portal bridging |
| 4 | Cirrhosis | 4 | Probable or definite cirrhosis | 4 | Cirrhosis | 4 | Early or definite cirrhosis | 4 | Fibrous expansion of most portal areas with marked bridging (portal-portal as well as portal-central ) |
| | | | | | | | 5 | Marked bridging (portal-portal, or portal-central, or both) with occasional nodules (incomplete cirrhosis) |
| | | | | | | | 6 | Probable or definite cirrhosis |
Computer image analysis can be used to determine the collagen proportional area of the stained sections of liver tissue. Quantitative assessment of liver fibrosis (qFibrosis) based on two-photon second harmonic generation can automatically measure the collagen area and the morphological features in unstained liver tissue sections, with high reproducibility and accuracy.101 Chinese researchers recently developed a P-I-R classification for liver fibrosis. Based on the width and shape of fibrous septa, this system qualitatively subdivides fibrosis with an Ishak score ≥3 into predominantly progressive (P), intermediate (I), and predominantly regressive (R) liver fibrosis. Therefore, the merit of this classification is to judge the dynamic trend of liver fibrosis evolution.102
Clinical diagnosis
According to the results of serological, virological, biochemical, imaging, and pathological tests as well as other auxiliary examinations, chronic HBV infection can be classified into:
Chronic HBV carrier state
This is also known as HBeAg-positive chronic HBV infection.103,104 Patients are in the immune tolerance phase and are generally younger. They are positive for HBeAg, with high levels of HBV DNA (usually >2×107 IU/mL) and serum HBsAg (usually >1×104 IU/mL). However, serum ALT and AST levels are persistently normal (three follow-ups within 1 year, ≥3 months apart), and liver biopsy shows no obvious necroinflammation or fibrosis. In the absence of liver biopsy, factors such as age, HBV DNA level, HBsAg level, noninvasive liver fibrosis tests, and imaging examination should be considered to help make a diagnosis.
HBeAg-positive CHB
Patients are in the immune clearance phase and are seropositive for HBsAg and HBeAg. HBV DNA levels are high (usually >2×104 IU/mL). ALT levels are persistently or intermittently abnormal, or liver biopsy reveals obvious necroinflammation, or fibrosis, or both (≥G2/S2).
Inactive HBsAg carrier state105,106
This is also known as HBeAg-negative chronic HBV infection. Patients are in the immune control phase. They are positive for HBsAg and anti-HBe and negative for HBeAg. HBV DNA levels are <2,000 IU/mL, and HBsAg levels are <1,000 IU/mL. ALT and AST levels are persistently normal (three follow-ups within 1 year, ≥3 months apart). Imaging examination shows no signs of cirrhosis. Liver biopsy shows a histological activity index score <4, or lesions are mild using other semi-quantitative scoring systems.
HBeAg-negative CHB
This is the reactivation phase. Patients are positive for HBsAg and persistently negative for HBeAg, which is often accompanied by anti-HBe positivity. HBV DNA levels are usually ≥2,000 IU/mL. ALT levels are persistently or intermittently abnormal, or liver biopsies show obvious necroinflammation, or fibrosis, or both (≥G2/S2).
Occult HBV infection (OBI)107
Patients are negative for HBsAg in serum but positive for HBV DNA in serum or liver tissue, or both. A total of 80% of OBI patients might be seropositive for anti-HBs, and anti-HBe or anti-HBc, or both, which is designated as seropositive OBI; however, 1–20% of OBI patients are seronegative for all serological indicators, which is designated as seronegative OBI. Its mechanism has not been determined. One possible explanation is that HBsAg disappears after apparent (acute or chronic) HBV infection, and HBV DNA levels are usually very low in the serum or liver tissue, without obvious liver tissue damage. Another possibility is mutations in the S gene region of HBV, which makes HBsAg undetectable by currently available commercial kits. Serum HBV DNA levels are usually high, which might be accompanied by significant liver histopathological changes. These patients can transmit HBV to recipients through blood transfusion or organ transplantation and might experience reactivation of HBV if they are immunosuppressed.
Hepatitis B cirrhosis108,109
The diagnosis of hepatitis B cirrhosis should meet the first and the second criteria of the following pathological diagnosis or the first and the third criteria of the following clinical diagnosis.
Patients are HBsAg-positive, or HBsAg-negative, anti-HBc positive and have a clear history of chronic HBV infection (presence of HBsAg >6 months), and other causes have been excluded.
Liver biopsy suggests cirrhosis.
Patients meet ≥2 of the following five criteria, and noncirrhotic portal hypertension has been excluded: (1) imaging examination shows signs of cirrhosis, or portal hypertension, or both; (2) endoscopy shows esophagogastric varices; (3) liver stiffness measurements suggest cirrhosis; (4) blood biochemical tests show reduced albumin levels (<35 g/L), or prolonged PT, or both (>3 s longer than controls); and (5) routine blood tests show platelet count <100×109/L.
Clinically, cirrhosis is divided into the compensated stage and decompensated stage based on the presence or absence of serious complications, such as ascites, esophagogastric variceal bleeding, and hepatic encephalopathy: (1) compensated cirrhosis; patients who are pathologically or clinically diagnosed with cirrhosis but have never had serious complications, such as ascites, esophagogastric variceal bleeding, or hepatic encephalopathy, could be diagnosed as having compensated cirrhosis and most of them have Child-Pugh A liver function; and (2) decompensated cirrhosis; if patients with cirrhosis develop serious complications, such as ascites, esophagogastric variceal bleeding, or hepatic encephalopathy, they are diagnosed as decompensated cirrhosis.110 Most of them have Child-Pugh B or C liver function.
Recently, to more accurately predict the progression, death risk, or treatment effect of patients with cirrhosis, some researchers have suggested dividing cirrhosis into five stages,111 between which stages 1 and 2 are compensated cirrhosis, and stages 3–5 are decompensated cirrhosis: stage 1, no varicose veins or ascites; stage 2, varicose veins, no bleeding or ascites; stage 3, ascites, no bleeding, with or without varicose veins; Stage 4, bleeding, with or without ascites; and stage 5, sepsis.
Due to the advances in antiviral therapy, many patients with decompensated cirrhosis could be reversed to compensated cirrhosis following treatment. The reversal is characterized by improved liver cell function, such as higher albumin levels, shorter PT than before, the disappearance of serious complications, such as ascites and hepatic encephalopathy, and long-term survival without liver transplantation. This phenomenon is called recompensation of cirrhosis; however, there is no accurate definition and uniform diagnostic criteria for this concept.
Indications for antiviral therapy
Patients should be assessed for the risk of disease progression to determine whether to start antiviral therapy based on a comprehensive analysis of serum HBV DNA levels, ALT levels, the severity of liver disease, as well as their age, family history, and concomitant diseases.6,112,113 Dynamic assessment is more meaningful than a single test (Fig. 1).
For patients with chronic HBV infection with positivity for serum HBV DNA, antiviral therapy is indicated if their ALT levels are persistently abnormal (>ULN) and other causes of ALT elevation have been excluded.
Other causes of ALT elevation include infection by other pathogens, drug-induced liver injury, alcoholic hepatitis, nonalcoholic steatohepatitis, autoimmune liver disease, and systemic diseases that involve the liver. In addition, the possibility of drug-induced temporarily normal ALT levels should be ruled out.
For patients with clear evidence of cirrhosis, antiviral treatment should be initiated if HBV DNA can be detected, regardless of ALT levels and HBeAg status. For patients with decompensated cirrhosis, antiviral therapy is indicated if HBV DNA is undetectable but HBsAg is positive.
Patients with seropositive HBV DNA and normal ALT levels are at a high risk of disease progression and antiviral therapy is indicated if they meet any of the following criteria: (1) obvious liver inflammation on liver biopsy (≥G2) or fibrosis (≥S2); (2) persistently normal ALT levels (tested every 3 months for 12 months) but with a family history of cirrhosis or liver cancer, and >30 years of age; (3) persistently normal ALT levels (tested every 3 months for 12 months), no family history of cirrhosis or liver cancer, but >30 years of age with noninvasive tests for liver fibrosis or liver biopsy revealing obvious liver inflammation or fibrosis; a (4) HBV-related extrahepatic manifestations (e.g., glomerulonephritis, vasculitis, polyarteritis nodosa, and peripheral neuropathy).
Recommendation 6: If serum HBV DNA is positive, ALT levels are persistently abnormal (>ULN), and other causes have been excluded, antiviral therapy is indicated (B1).
Recommendation 7: Antiviral therapy is indicated for HBV-related compensated cirrhosis patients with positive serum HBV DNA and HBV-related decompensated cirrhosis patients with positive HBsAg (A1).
Recommendation 8: If patients are seropositive for HBV DNA with normal ALT levels, antiviral therapy is indicated when they meet any one of the following criteria: (1) liver biopsy suggests obvious inflammation, or fibrosis, or both (G ≥2, or S ≥2, or both) (A1); (2) a family history of HBV-related cirrhosis or liver cancer and age >30 years-old (B1); (3) noninvasive tests or liver biopsy revealing obvious liver inflammation or fibrosis in those with persistently normal ALT levels and age >30 years-old (A1); and (4) HBV-related extrahepatic manifestations (e.g., HBV-related glomerulonephritis) (B1).
Recommendations on antiviral therapy for special populations
Patients with poor response
CHB patients
After treatment with ETV, TDF, or TAF for 48 weeks, if HBV DNA is >2×103 IU/mL, and excluding compliance and detection errors, NA-based treatment regimens should be adjusted (those using ETV could be switched to TDF or TAF,162,163 and those using TDF or TAF could be switched to ETV), or combination therapy could be used (ETV combined with TDF or TAF). Peg-IFN-α therapy can also be used in combination.
Patients with HBV-related cirrhosis
After treatment with ETV, TDF, or TAF for 24 weeks, if HBV DNA is >2×103 IU/mL, and excluding compliance and detection errors, NA-based treatment regimens could be adjusted (those using ETV could be switched to TDF or TAF, and those using TDF or TAF could be switched to ETV), or combination therapy might be used (ETV combined with TDF or TAF).
Patients treated with chemotherapeutic or immunosuppressive agents
Chemotherapy or immunosuppressive therapy in CHB patients might cause HBV reactivation and might lead to liver failure or even death in severe cases. HBV reactivation occurs after antitumor therapy in approximately 20–50% of HBsAg-positive, anti-HBc-positive tumor patients, and in 8–18% of HBsAg-negative, anti-HBc-positive tumor patients.164,165 Prophylactic antiviral therapy can significantly reduce the incidence of hepatitis B reactivation.166,167 ETV, TDF, or TAF, which are potent antivirals with minimal resistance, are recommended.168–170
All patients that receive chemotherapy or immunosuppressive therapy should be routinely screened for HBsAg and anti-HBc before starting treatment.
HBsAg-positive patients should be given NA therapy (usually 1 week) before or when they start receiving immunosuppressive or chemotherapeutic agents.6,171,172
In addition, HBsAg-negative, anti-HBc-positive patients need prophylactic antiviral therapy if they are positive for HBV DNA;112 if HBV DNA is negative, ALT levels, HBV DNA, and HBsAg should be monitored every 1–3 months. Antiviral therapy should be initiated immediately when HBV DNA or HBsAg becomes positive.112,173
For HBsAg-negative and anti-HBc-positive patients, the use of B-cell monoclonal antibodies or hematopoietic stem cell transplantation is associated with a high-risk of HBV reactivation.174,175 The prophylactic use of antiviral drugs is recommended.112,165,168,176,177
For patients with CHB or cirrhosis that are treated with chemotherapy and immunosuppressants, the course of NA treatment, follow-up monitoring, and drug withdrawal are the same as those for patients with CHB or cirrhosis that receive no chemotherapy or immunosuppressants. For patients with chronic HBV infection in the immune tolerance or immune control phases, or HBsAg-negative, anti-HBc-positive patients that require the prophylactic use of NAs, treatment with ETV, TDF, or TAF should be continued for 6–12 months after the end of chemotherapy and immunosuppressive therapy.6,168,178
For patients that receive B-cell monoclonal antibodies or undergo hematopoietic stem cell transplantation, NAs could be discontinued at least 18 months after the end of immunosuppressive therapy.179,180 HBV could recur or even worsen after NAs are withdrawn. Patients should be followed up for 12 months, during which HBV DNA should be monitored every 1–3 months.
Pregnancy
Women of childbearing age or women that are preparing to become pregnant should be screened for HBsAg, and HBV DNA should be tested for HBsAg-positive patients.181 Peg-IFN-α treatment should be initiated before pregnancy if antiviral therapy is indicated, and antiviral therapy should be completed 6 months before pregnancy. Reliable contraceptive measures should be taken during treatment. If peg-IFN-α is not indicated or fails, TDF could be used for antiviral therapy. For patients diagnosed with CHB for the first time during pregnancy, treatment indications are the same as those for other CHB patients, and TDF could be used for antiviral therapy. Pregnant women with CHB who started taking antiviral drugs before or during pregnancy should continue antiviral therapy after delivery, and based on virological responses, decide whether to continue the original treatment regimen or change to other NAs or peg-IFN-α.
For patients with unexpected pregnancy during antiviral therapy, it is recommended that they continue their pregnancy if they are taking TDF. Patients do not have to terminate the pregnancy if they are taking ETV, and it is suggested that they switch to TDF instead. If pregnant patients are receiving IFN-α treatment, they should be informed (and their family members) of the associated risks, and whether or not to continue the pregnancy should be decided by patients themselves; if the pregnancy choice is to continue, patients should change to TDF treatment.
High levels of serum HBV DNA is a high-risk factor for mother-to-child transmission. If HBV DNA levels are >2×105 IU/mL in the second and third trimesters of pregnancy,182 the patients should be informed of the associated risks and their consent should be obtained to start antiviral therapy at 24–28 weeks of the pregnancy using TDF or LdT.183,184 Breastfeeding is not a contraindication for TDF therapy.185,186 Pregnant women taking NAs at the immune tolerance phase could discontinue NAs immediately after delivery or continue for another 1–3 months. Approximately 17.2–62% of patients might develop hepatitis flares after discontinuation, which usually occurs within 24 weeks.187–189 Postpartum monitoring is needed. Blood biochemical indexes for the liver and HBV DNA should be rechecked 4–6 weeks after delivery. If the biochemical markers for the liver are normal, they should be followed up every 3 months until 6 months after delivery. If patients develop hepatitis flares, antiviral therapy is indicated.
Fertility issues for male patients that receive antiviral therapy: Male patients treated with IFN-α might consider having children 6 months after drug withdrawal. No evidence is currently available that indicates NA therapy harms sperm in male patients that receive NA therapy. Male patients should be informed of the potential risks when they consider having children.
Pediatric patients
If children with HBV infection are in the immune tolerance phase, antiviral therapy is not considered. Antiviral therapy should be initiated as soon as possible for children with chronic hepatitis or cirrhosis. Antiviral therapy for children with CHB can significantly inhibit HBV DNA replication and increase the chance of ALT normalization and HBeAg seroconversion.190 However, the safety and resistance issues associated with long-term treatment should be concerned.112,191,192
The drugs approved by the USA’s Food and Drug Administration (FDA) for the treatment of pediatric patients include IFN-α (aged ≥1 year), ETV (aged ≥2 years), and TDF (aged ≥2 years and body weight ≥10 kg).6,190 China has approved TAF for adolescents (aged ≥12 years and body weight ≥35 kg). Peg-IFN-α-2a could be used in CHB children aged ≥5 years.6
HBeAg-positive CHB patients with elevated ALT levels should be treated with a finite course of IFN-α or peg-IFN-α-2a therapy to achieve HBeAg conversion.178,193 Alternatively, they could be treated with ETV, TDF, or TAF. The recommended dose of IFN-α for pediatric patients is 3–6 million U/m2, three times a week. The maximum dose should not exceed 10 million U/m2, and the recommended duration of treatment is 24–48 weeks. Peg-IFN-α-2a should be dosed at 180 µg/1.73 m2, with a treatment course of 48 weeks.194 The doses of ETV, TDF, or TAF refer to the recommendations of the USA’s FDA and WHO, and drug labels (Table 6).8,190,193
Table 6Recommended doses of NAs for children
| Drug | Body weight (kg) | Dose (mg/d) |
|---|
| ETV (aged ≥2 years, and body weight ≥10 kg; use adult dose if body weight >30 kg) | 10–11 | 0.15 |
| >11–14 | 0.20 |
| >14–17 | 0.25 |
| >17–20 | 0.30 |
| >20–23 | 0.35 |
| >23–26 | 0.40 |
| >26–30 | 0.45 |
| > 30 | 0.50 |
| TDF | | |
| Aged ≥2 years and body weight ≥17 kg, who can take tablets orally | 17–22 | 150 |
| 22–28 | 200 |
| 28–35 | 250 |
| ≥35 | 300 |
| Aged ≥2 years and body weight ≥10 kg; those who cannot take tablets orally can be given powder using a special spoon (40 mg/spoon) | 10–12 | 80 (2 spoons) |
| 12–14 | 100 (2.5 spoons) |
| 14–17 | 120 (3 spoons) |
| 17–19 | 140 (3.5 spoons) |
| 19–22 | 160 (4 spoons) |
| 22–24 | 180 (4.5 spoons) |
| 24–27 | 200 (5 spoons) |
| 27–29 | 220 (5.5 spoons) |
| 29–32 | 240 (6 spoons) |
| 32–34 | 260 (6.5 spoons) |
| 34–35 | 280 (7 spoons) |
| ≥35 | 300 (7.5 spoons) |
| TAF (aged ≥12 years) | ≥35 | 25 |
For children with CHB or cirrhosis that receive therapy with IFN-α or peg-IFN-α-2a but fail to achieve HBeAg seroconversion or HBeAg-negative status, NAs should be used for treatment.178
Patients with renal injury
High-risk factors for renal injury include ≥1 of the following: decompensated cirrhosis; eGFR <60 mL/min; poorly controlled hypertension; proteinuria; uncontrolled diabetes; active glomerulonephritis; concomitant use of nephrotoxic drugs; or history of solid organ transplantation.112 When there are high-risk factors for renal injury, the changes in renal function should be monitored during the use of any NA. If ADV or TDF is used for treatment, serum creatinine and blood phosphorus levels should be monitored regularly, regardless of the presence or absence of high-risk factors for renal injury.195,196
For patients with chronic kidney disease, renal insufficiency, or who receive renal replacement therapy, ETV or TAF is recommended as the first-line anti-HBV therapy; LdT could also be chosen for antiviral therapy, where appropriate. ADV or TDF is not recommended.142,197 When TAF is used in patients without HIV coinfection, no dose adjustment is necessary when eGFR is ≥15 mL/min; however, the doses of other NAs currently on the market need to be adjusted when eGFR is <50 mL/min. Dosing adjustments should refer to drug labels.
ETV or TAF could be used as prophylactic or therapeutic drugs for HBsAg-positive patients that receive kidney transplantation. Because of the increased risk of rejection, kidney transplant patients should avoid IFN-α or peg-IFN-α therapy.
HBV-related glomerulonephritis could be treated with NA therapy, and ETV or TAF is recommended.198
For patients that have been treated with ADV or TDF, it is recommended that they should change to ETV or TAF if kidney or bone disease occurs, or if other high-risk factors are involved.197
Recommendation 15: For CHB patients, after 48 weeks of treatment with ETV, TDF, or TAF, of HBV DNA is >2×103 IU/mL, NAs treatment regimens should be adjusted when excluding compliance and detection errors. Those using ETV could change to TDF or TAF, and those using TDF or TAF could change to ETV, or combination therapy might be used (ETV combined with TDF or TAF) (C2). Peg-IFN-α therapy could be used in combination (B1).
For patients with HBV-related cirrhosis, after treatment with ETV, TDF, or TAF for 24 weeks, of their HBV DNA is >2×103 IU/mL, and excluding compliance and detection errors, NAs treatment regimens could be adjusted. Those using ETV could change to TDF or TAF, and those using TDF or TAF could change to ETV, or combination therapy might be used (ETV combined with TDF or TAF) (C2).
Recommendation 16: All patients that receive chemotherapy or immunosuppressive therapy should be routinely screened for HBsAg and anti-HBc before starting treatment (A1). For HBsAg-positive patients, antiviral therapy should be given 1 week before or when they start to receive immunosuppressive therapy or chemotherapy (A1), and ETV, TDF, or TAF should be used (B1). For HBsAg-negative and anti-HBc-positive patients, antiviral therapy with ETV, TDF, or TAF is recommended if they receive B-cell monoclonal antibodies or undergo hematopoietic stem cell transplantation (B1).
Recommendation 17: When patients with chronic HBV infection attempt pregnancy or have antiviral indications during pregnancy, TDF could be used when informed consent has been obtained (B1).
Recommendation 18: For patients with unexpected pregnancy during antiviral therapy it is recommended that they continue their pregnancy if they are taking TDF. Patients do not have to terminate the pregnancy if they are taking ETV and it is suggested that they change to TDF instead (B1). If patients are receiving IFN-α treatment, they (and their family members) should be informed of the associated risks, and whether or not to continue the pregnancy should be decided by patients themselves; if they decide to continue, they should change to TDF treatment (C2).
Recommendation 19: If HBV DNA levels are >2×105 IU/mL during the second and third trimesters of pregnancy, patients should be informed of the associated risks and could start antiviral therapy at 24–28 weeks of pregnancy using TDF or LdT when they give informed consent (A1). Pregnant women in the immune tolerance phase should stop medication immediately after delivery or after 1–3 months of treatment. Breastfeeding is not a contraindication for TDF treatment (C2). Blood biochemical indexes for the liver function and HBV DNA levels should be tested at least every 3 months until 6 months after delivery after drug withdrawal. Patients that develop hepatitis flares should start antiviral therapy immediately (A2).
Recommendation 20: For children with advanced liver disease or cirrhosis, antiviral therapy should be given in time, but safety and resistance issues associated with long-term antiviral treatment should be considered. IFN-α treatment could be considered for children aged ≥1 year, ETV or TDF for children aged ≥2 years, peg-IFN-α-2a for children aged ≥5 years. and TAF treatment for children aged ≥12 years (A1).
Recommendation 21: For patients with chronic kidney disease, renal insufficiency, or who receive renal replacement therapy, ETV or TAF is recommended as the first-line anti-HBV therapy. Alternatively, LdT could be used for antiviral therapy, where appropriate. ADV or TDF is not recommended (B1). The changes in renal function should be monitored during the use of any NAs for CHB patients at a high-risk of kidney injury. For patients that have been treated with ADV or TDF, it is recommended that they switch to ETV or TAF if they develop kidney or bone disease or present with other high-risk factors (B1).
Patients with coinfection of HBV and HCV
All people that are HBsAg-positive should be screened for anti-HCV. If they are positive, they need further testing for HCV RNA. Those who test positive for HCV RNA should receive DAA therapy. These patients are at risk of HBV reactivation. Therefore, it is recommended that they receive antiviral therapy with ETV, TDF, or TAF during and within 3 months after the end of anti-HCV therapy and they should be closely monitored.112
In addition, HBsAg-negative and anti-HBc-positive patients are at risk of HBV reactivation during treatment of hepatitis C with DAAs. Serum HBV DNA levels and HBsAg should be monitored monthly. If HBsAg seroreversion occurs, antiviral therapy is recommended.112
Recommendation 22: When a DAA is used to treat HCV in patients with coinfection of HCV and HBV, NA treatment should be administered to prevent HBV reactivation if HBsAg is positive. NA treatment could be withdrawn 12 weeks after the end of DAA treatment (B2). HBsAg-negative, anti-HBc-positive patients should be closely monitored for HBV DNA and HBsAg levels during DAA therapy. If HBsAg seroreversion occurs, NA therapy is recommended (B2).
Patients with coinfection of HBV and HIV
Antiretroviral therapy (commonly referred to as ART) should be initiated as soon as possible if there is no contraindication for anti-HIV therapy, regardless of CD4+T lymphocyte count. HIV/HBV co-infected patients should be treated for both viral infections at the same time. The highly active anti-retroviral therapy (HAART) regimen should include two drugs active against HBV, preferably TDF or TAF + LAM or emtricitabine (FTC) (TDF+FTC and TAF+FTC are available as a mixture). HBV-related markers, such as HBV DNA, liver biochemical indicators, and liver imaging should be monitored during treatment. For HIV/HBV co-infected patients, a treatment regimen for hepatitis B that contains only one NA against HBV is not recommended (TDF, LAM, ETV, LdT, ADV).199,200
The following should be noted for patients with renal insufficiency: (1) if the creatinine clearance rate is <60 mL/min, avoid use of TDF; and (2) if the creatinine clearance rate is between 30 mL/min and 50 mL/min, TAF+ (FTC or LAM) could be considered in the regimen. However, TAF has not been approved for use yet in patients with a creatinine clearance rate <30 mL/min. Finally, (3) when TDF/TAF cannot be used, ETV should be added to the HAART regimen. For pregnant women with HIV/HBV co-infection, the recommended regimen should include LAM (FTC)+TDF.201
Recommendation 23: For people who are co-infected with HBV and HIV, it is recommended that a combination of antiviral drugs effective for both HIV and HBV be chosen (A1).
Patients with HBV-related liver failure
Patients with HBV-related acute, subacute, acute-on-chronic, and chronic liver failure are associated with high mortality. If HBsAg is positive, antiviral therapy is indicated.
Anti-HBV therapy can improve the long-term prognosis of HBV-related acute-on-chronic liver failure (ACLF).202,203 Several clinical studies have confirmed that both ETV and LAM can effectively reduce the mortality of ACLF.204,205 Meta-analyses have shown that ETV is superior to LAM for the treatment of HBV-related ACLF.205,206 Small cohort clinical studies have found that HBV-related ACLF can benefit from the use of LdT and TDF.207,208 Compared with TDF, TAF can reduce nephrotoxicity and maintain antiviral efficacy,142 but no definite clinical evidence is available to support the use of TAF for liver failure. Early rapid reduction of HBV DNA levels is key to treatment.204,207 If HBV DNA levels can be reduced by 2 lg IU/mL within 2–4 weeks, survival can be improved.206,207 Fast-acting NAs with high potency and minimal resistance (ETV, TDF, or TAF) should be chosen for antiviral therapy.209 Antiviral therapy should be continued for long periods after patients with liver failure recover.
Recommendation 24: For patients with HBV-related acute, subacute, acute-on-chronic, and chronic liver failure, it is recommended that they should receive antiviral therapy with ETV, TDF, or TAF if they are positive for HBsAg (A1).
Patients with HBV-related HCC
HBV DNA-positive HCC patients that receive anti-HBV treatment could reduce the recurrence of HCC after surgery and improve the overall survival rate.210–216 Fast-acting NAs with high potency (ETV, TDF, or TAF) should be chosen for antiviral therapy. Patients without contraindications could use IFN-α.
HCC patients that are HBsAg-positive but HBV DNA-negative might experience HBV reactivation when undergoing liver resection, transcatheter arterial chemoembolization, radiotherapy, or systemic chemotherapy.217–221 ETV, TDF, or TAF are recommended for antiviral therapy.
Recommendation 25: Patients with HBV-related HCC are recommended to use ETV, TDF or TAF for antiviral therapy if they are positive for HBsAg (A1).
Liver transplant patients
For patients that undergo liver transplantation for HBV-related diseases (including liver failure and HCC), anti-HBV regimens should be rationally selected to reduce the risk of reinfection of HBV in the transplanted liver. The design of treatment regimens mainly depends on the major risk factor for reinfection, i.e. HBV DNA levels before transplantation.
A negative HBV DNA quantification test before transplantation suggests a low risk of reinfection. High potency NAs with minimal resistance, such as ETV, TDF, or TAF, should be used as early as possible before surgery to prevent HBV reactivation. There is no need to use HBIG after surgery.222,223 Positive HBV DNA testing before transplantation suggests a high-risk of reinfection. NAs with high potency and minimal resistance should be used as early as possible before surgery to reduce HBV DNA levels; HBIG should be injected intravenously during the anhepatic phase. After surgery, low-dose HBIG should be used in combination with NAs for 0.5–1.0 year, followed by the use of NAs alone.222,224,225 A recent study found that a shortened course of HBIG was effective in patients treated with ETV.226 If patients have already used other NAs, HBV DNA should be closely monitored to detect drug resistance and adjust the regimen if necessary. In addition, hepatitis B vaccination was reported to prevent recurrence after liver transplantation, but its clinical use remains controversial.227
Recommendation 26: For patients that undergo liver transplantation for HBV-related infections, it is recommended that they start antiviral therapy with ETV, TDF, or TAF before transplantation if they are positive for HBsAg (A1).