The Hepatology Section of the Chinese Medical Association and the Infectious Diseases Section of the Chinese Medical Association Chronic hepatitis B is one of the common chronic infectious diseases in China, which seriously endangers people’s health. To further standardize the prevention, diagnosis and treatment of chronic hepatitis B, the Hepatology Section of the Chinese Medical Association and the Infectious Diseases Section of the Chinese Medical Association have organized relevant domestic experts to develop this Guideline based on the principles of evidence-based medicine with reference to the latest research results at home and abroad. The evidence on which the recommended opinions are based is divided into 3 levels and 5 grades [1], which are indicated in the text by italicized Roman numerals in parentheses. These Guidelines are intended only to help physicians make sound decisions about the diagnosis and prevention of hepatitis B. They are not mandatory; nor can they include or address all issues in the diagnosis and treatment of chronic hepatitis B. Therefore, clinicians should be fully aware of the best clinical evidence and available medical resources for this disease when addressing a specific patient, and should develop a reasonable treatment plan based on their knowledge and experience, taking into account the patient’s specific condition and his or her wishes in a comprehensive manner. Due to the rapid progress in research on chronic hepatitis B, this Guideline will be updated and improved as needed. The hepatitis B virus (HBV) belongs to the hepadna viridae family, with a genome of about 3.2 kb in length and partially double-stranded cyclic DNA. After HBV invades the body, it binds to the receptor on the hepatocyte membrane, sheds the envelope and penetrates into the hepatocyte plasma, then sheds the capsid and partially double-stranded cyclic DNA enters the hepatocyte nucleus. HBV DNA enters the nucleus of hepatocytes, and under the action of host enzymes, the negative-stranded DNA is used as a template to extend the positive strand and repair the gap region in the positive strand, forming covalent closed-loop DNA (cccDNA), and then cccDNA is used as a template and transcribed into several mRNAs of different lengths under the action of host RNA polymerase II, of which the 3.5-kb mRNA contains all the genetic information on the HBV The latter enters the hepatocyte cytoplasm as a template and synthesizes negative-stranded DNA under the action of HBV DNA reverse transcriptase; then the negative-stranded DNA is used as a template to synthesize positive-stranded DNA, forming part of the daughter double-stranded circular DNA, which is finally assembled into complete HBV and released outside the hepatocyte. The cytoplasmic part of the daughter double-stranded circular DNA can also enter the nucleus of the hepatocyte to form cccDNA and continue replication. cccDNA has a long half-life and is difficult to be completely removed from the body [1,2]. HBV contains four partially overlapping open reading frames (ORFs), namely the pre-S/S region, the pre-C/C region, the P region and the X region. The pre-S/S region encodes three envelope proteins: large (pre-S1, pre-S2 and S), medium (pre-S2 and S), and small (S); the pre-C/C region encodes HBeAg and HBcAg; the P region encodes polymerase; and the X region encodes X protein. Variants in the pre-C region and the basic core promoter (BCP) can produce HBeAg-negative variants. The most common variant in the pre-C region is the G1896A point mutation, which forms the stop codon (TAG) and does not express HBeAg. The most common variant in the BCP region is the combined A1762T/G1764A point mutation, which selectively represses transcription of pre-C mRNA and reduces HBeAg synthesis [3]. P-gene variants are mainly seen in the POL/RT gene fragment (349 to 692aa, i.e., rt1 to rt344). In lamivudine treatment, the most common is the tyrosine-methionine-aspartate-aspartate (YMDD) variant, i.e., the variant from YMDD to YIDD (M204I) or YVDD (M204V), and often accompanied by the L180M variant, which gradually becomes the dominant strain resistant to lamivudine due to drug selection [4](I). S-gene variants can lead to occult HBV infection, which is characterized by negative serum HBsAg but still low levels of HBV replication (serum HBV DNA is often < 104 copies/ml) [5]. HBV can be classified into 8 genotypes from A to H based on HBV whole gene sequence differences ≥ 8% or S region gene sequence differences ≥ 4%; each genotype can be divided into different genetic subtypes. patients with genotype A chronic hepatitis B have a higher response rate to interferon therapy than genotype D, and patients with genotype B have a higher response rate than genotype C [6](I). Whether genotype affects the efficacy of nucleoside analogs has not been determined. HBV is prone to mutation. In HBV-infected patients, a cluster of related mutant strains of virus, called quasispecies, is often formed with one dominant strain, the exact clinical significance of which needs to be further confirmed. HBV is highly resistant, but 65°C for 10 h, boiling for 10 min or high pressure steam can inactivate HBV. ethylene oxide, glutaraldehyde, peroxyacetic acid and iodophor also have a good inactivation effect. Epidemiology Hepatitis B (referred to as hepatitis B) is a worldwide epidemic, but the intensity of HBV prevalence varies greatly from region to region. According to the World Health Organization, about 2 billion people worldwide have been infected with HBV, 350 million of whom are chronically HBV-infected, and about 1 million people die each year from liver failure, cirrhosis, and primary hepatocellular carcinoma (HCC) due to HBV infection [7]. China is a highly endemic area for HBV, and the HBsAg positivity rate in the general population is 9.09%. The HBsAg positivity rates in the vaccinated and unvaccinated population were 4.51% and 9.51%, respectively [8] (III). The prevalent HBV serotypes in China are mainly adrq+ and adw2, with a few ayw3 (mainly seen in Xinjiang, Tibet and Inner Mongolia); the genotypes are mainly C and B [9]. HBV is mainly transmitted via blood and blood products, mother-to-child, via broken skin and mucous membranes, and sexual contact [7]. Perinatal (birth) transmission is the main mode of mother-to-child transmission, mostly from exposure to the blood and body fluids of HBV-positive mothers during delivery (I). Transdermal mucosal transmission occurs mainly from the use of medical devices, syringes, invasive diagnostic and surgical procedures without strict sterilization [1,10] (II-2), and intravenous drug abuse (I). Others such as tattooing, ear piercing, accidental exposure during the work of medical personnel, and sharing of razors and toothbrushes can also be transmitted (III). Sexual contact with HBV-positive people, especially those with multiple sexual partners, has an increased risk of HBV infection (I). Due to the strict implementation of HBsAg screening for blood donors, HBV infection caused by blood transfusion or blood products has rarely occurred. HBV transmission via blood-sucking insects (mosquitoes, bedbugs, etc.) has not been confirmed [27]. Third, the natural history of HBV infection in humans, the virus persists for 6 months and is still not cleared is called chronic HBV infection. Age at the time of infection is the most important factor influencing chronicity. Among those infected with HBV during the perinatal (birth) period and infancy, 90% and 25%-30%, respectively, will develop chronic infection [11](I); the natural history of their HBV infection can generally be divided into three phases, namely, the immune tolerance phase, the immune clearance phase, and the inactive or low (non)replication phase [12]. The immune tolerance phase is characterized by active HBV replication, positive serum HBsAg and HBeAg, high HBV DNA titers (>105 copies/ml), normal serum alanine aminotransferase (ALT) levels, and no significant abnormalities in liver histology. The immune clearance phase is characterized by a serum HBV DNA titer >105 copies/ml, but is generally lower than the immune tolerance phase, with persistent or intermittent elevation of ALT/aspartate aminotransferase (AST) and necroinflammation on liver histology. The inactive or low (non) replication phase is characterized by HBeAg negativity/anti-HBe positivity, undetectable HBV DNA (PCR method) or below the threshold, normal ALT levels, and no or mild inflammation on liver histology. In adolescents and adults infected with HBV, only 5-10% develop chronic, generally without an immune tolerance period. The early phase is the immune clearance phase, which manifests as active chronic hepatitis B. The later phase is the inactive or low (non)replication phase, where liver disease is in remission. Some patients with HBV infection, either during the perinatal and infancy periods or in adolescence and adulthood, may become reactive and develop positive HBeAg in their inactive or low (non)-replicating HBV infections, or may have pre-C or C region promoter mutations and become reactive but HBeAg negative, both of which are manifested as active chronic hepatitis B. The proportion of children and adults with HBeAg-positive chronic hepatitis B who develop inactive or low (non) replication stage after 5 and 10 years is 50% and 70%, respectively [13,14] (II-3,II-2). The natural history of chronic HBV-infected patients with inactive or low (non)-replicating stages is not well studied in China and the Asia-Pacific region, but it is well documented that these patients can have recurrent episodes of hepatitis [8]. A prospective study of 684 cases of chronic hepatitis B showed that the estimated annual incidence of developing cirrhosis in patients with chronic hepatitis B was 2.1% [15]. In another study of HBeAg-negative chronic hepatitis B with a mean follow-up of 9 years (1 to 18.4 years), the incidence of progression to cirrhosis and HCC was 23% and 4.4%, respectively [16,17]. High risk factors for developing cirrhosis include high viral load, persistent HBeAg positivity, high or repeatedly fluctuating ALT levels, alcoholism, and co-infection with HCV, HDV, or HIV [18-20] (I). the incidence of cirrhosis is higher in HBeAg-positive than in HBeAg-negative patients [1,10,15] (II-2). The annual incidence of cirrhosis loss in patients with chronic hepatitis B is about 3% and the 5-year cumulative incidence is about 16% [10](I). The 5-year morbidity and mortality rates for chronic hepatitis B, compensated and decompensated cirrhosis are 0% to 2%, 14% to 20% and 70% to 86%, respectively. The influencing factors include age, serum albumin and bilirubin levels, platelet count and splenomegaly [10] (II-2). Survival rates are higher in those with spontaneous or antiviral therapy followed by HBeAg seroconversion with persistent HBV DNA conversion and persistent normal ALT [10,21] (I,II-3,). HBV infection is an important correlate of HCC, and the incidence of HCC is significantly higher in those who are positive for both HBsAg and HBeAg than in those who are positive for HBsAg alone [22](II-2). High risk factors for HCC in patients with cirrhosis include male gender, age, alcoholism, aflatoxin, co-infection with HCV or HDV, persistent liver inflammation, persistent HBeAg positivity and persistent high levels of HBV DNA (≥105 copies/ml) [10](I). Approximately 25% of those infected before the age of 6 years will develop cirrhosis and HCC in adulthood [23] (II-2). However, a small proportion of patients with HCC associated with HBV infection have no evidence of cirrhosis. family history of HCC is also a relevant factor, but HBV viral load is more important in the same genetic background [24](II-3). IV. Prevention (I) Hepatitis B vaccine prevention Vaccination against hepatitis B is the most effective way to prevent HBV infection. The targets of hepatitis B vaccination are mainly newborns [25], followed by infants and high-risk groups (e.g., medical personnel, those who are frequently exposed to blood, staff of childcare institutions, organ transplant patients, frequent recipients of blood transfusions or blood products, immunocompromised individuals, those prone to trauma, family members of HBsAg-positive individuals, gay men or those with multiple sexual partners and intravenous drug addicts). A total of 3 doses of vaccine will be administered, according to the 0, 1 and 6 months procedure, i.e. after the first dose of vaccine, the second and third doses will be administered at 1 and 6 months intervals. Hepatitis B vaccination for newborns is given as early as possible, within 24 hours after birth. Vaccination is given intramuscularly in the anterior lateral thigh for infants, and intramuscularly in the middle deltoid muscle of the upper arm for children and adults. The dose of recombinant yeast hepatitis B vaccine is 5 μg or 10 μg for neonates and children, and 10 μg or 20 μg for adults; recombinant Chinese hamster oocyte (CHO) hepatitis B vaccine is 10 μg for neonates and children, and 20 μg for adults. 87.8% protection against mother-to-child transmission was achieved with hepatitis B vaccine alone [26] (II-3). For newborns of HBsAg-positive mothers, 10 μg of yeast hepatitis B vaccine should be administered as early as possible within 24 h after birth, along with hepatitis B immunoglobulin (HBIG) at different sites (preferably within 12 h after birth, and the dose should be ≥100 IU), which significantly improves the effectiveness of blocking mother-to-child transmission [10,26,27] (II-3). It is also possible to administer 1 dose of HBIG within 12 h of birth, followed by a second dose of HBIG 1 month later, along with 10 μg of hepatitis B vaccine, and 10 μg of hepatitis B vaccine 1 and 6 months apart, respectively [28]. The latter is less convenient than the former, but its protection rate is higher than that of the former. Newborns can be breastfed by HBsAg-positive mothers after receiving hepatitis B vaccine and HBIG within 12 h of birth [29] (III). Neonates of HBsAg-negative mothers can be immunized with 5 μg of yeast hepatitis B vaccine; 20 μg of yeast hepatitis B vaccine is recommended for adults. For those with low immune function or no response to immunization, the vaccination dose and number of shots should be increased; those who do not respond to the 3-dose immunization program can receive 3 more doses, and the anti-HBs in the serum should be tested 1 to 2 months after the second 3-dose hepatitis B vaccination to determine whether antibodies are produced. The protective effect of hepatitis B vaccination for those with antibody response generally lasts for at least 12 years, so there is no need for anti-HBs monitoring or booster immunization for the general population. However, anti-HBs monitoring can be performed in high-risk groups, and booster immunization can be given if anti-HBs is <10 mIU/ml [30](III). (II) Transmission route prevention Safe injection (including needles for needling) should be vigorously promoted, and medical instruments such as dental instruments and endoscopes should be strictly disinfected. Medical personnel should wear gloves when touching patients' blood, body fluids and secretions in accordance with the principle of standard precautions in hospital infection management. Haircuts, shaves, pedicures, piercings and tattoos in all service industries should also be strictly disinfected. Pay attention to personal hygiene, do not share razors and dental tools, etc. Provide proper sex education, and if the sexual partner is HBsAg positive, hepatitis B vaccination should be given; those who have multiple sexual partners should be checked regularly, strengthen management, and be advised to use condoms during sexual intercourse. For HBsAg-positive pregnant women, they should avoid amniocentesis, shorten the delivery time, ensure the integrity of the placenta, and minimize the exposure of the newborn to maternal blood. (iii) HBV prophylaxis after accidental exposure [31] After accidental exposure to the blood and body fluids of HBV-infected individuals, the following methods can be followed: 1. Serological testing HBV DNA, HBsAg, anti-HBs, HBeAg, anti-HBe, ALT and AST should be tested immediately and retested within 3 and 6 months. 2. Active and passive immunization If you have received hepatitis B vaccine and have known anti-HBs ≥ 10 mIU/ml, you may not have special treatment. If you have not received hepatitis B vaccine, or if you have received hepatitis B vaccine but the anti-HBs < 10 mIU/ml or the level of anti-HBs is unknown, you should immediately inject 200-400 IU of HBIG and receive hepatitis B vaccine at different sites at the same time. (iv) Management of patients and carriers When diagnosing patients with acute or chronic hepatitis B, medical personnel at all levels should promptly report to the local Center for Disease Control and Prevention (CDC) in accordance with the Law of the People's Republic of China on the Prevention and Control of Infectious Diseases, and should indicate whether it is acute hepatitis B or chronic hepatitis B. It is recommended that family members and other close contacts of patients be tested for serum HBsAg, anti-HBc, and anti-HBs, and that susceptible individuals (who are negative for all three markers) be vaccinated against hepatitis B. Patients with acute or chronic hepatitis B may be hospitalized or treated at home, depending on their condition. Medical devices and utensils used by patients (e.g. blood collection needles, acupuncture needles, surgical instruments, scratch needles, probes, endoscopes and stomatological drills) should be strictly disinfected, especially the disinfection of blood contaminants should be enhanced. For chronic HBV carriers and HBsAg carriers (see "V. Clinical Diagnosis" in this guideline), they can work and study as usual, except that they cannot donate blood and work in direct contact with food and caregivers, but follow-up should be strengthened. The level of infectivity of hepatitis B patients and carriers depends mainly on the level of HBV DNA in the blood, but not on the level of serum ALT, AST or bilirubin. The follow-up of patients and carriers of hepatitis B is described in this guideline "XXI. V. Clinical diagnosis Those who have been HBsAg positive for more than 6 months, or have a history of hepatitis B or HBsAg positivity and are still HBsAg positive, can be diagnosed as chronic HBV infection. Based on the serology, virology, liver function tests and other clinical and ancillary findings of HBV-infected patients, chronic HBV infection can be classified as: (a) Chronic hepatitis B 1. HBeAg-positive chronic hepatitis B Serum HBsAg, HBV DNA and HBeAg positive, anti-HBe negative, persistent or recurrent elevation of serum ALT, or hepatitis lesions on liver histological examination. 2. HBeAg-negative chronic hepatitis B Serum HBsAg and HBV DNA positive, HBeAg negative, anti-HBe positive or negative, serum ALT persistently or repeatedly abnormal, or hepatitis lesions on liver histological examination. The above two types of chronic hepatitis B can also be further classified as mild, moderate and severe depending on liver function tests and other clinical and ancillary examination findings (see the 2001 Prevention and Treatment Program for Viral Hepatitis [32]) (ii) Hepatitis B cirrhosis Hepatitis B cirrhosis is the result of the development of chronic hepatitis B. Hepatic histopathology shows diffuse fibrosis and pseudolobule formation, both of which must be present at the same time. Both must be present to make a pathological diagnosis. 1.Compensated cirrhosis refers to early cirrhosis, usually of Child-Pugh A grade. There may be mild weakness, loss of appetite or abdominal distension, ALT and AST may be abnormal, but there is no obvious manifestation of liver failure. There may be signs of portal hypertension, such as hypersplenism and mild esophagogastric fundic varices, but no bleeding from ruptured esophagogastric varices, no ascites and hepatic encephalopathy, etc. 2.Decompensated cirrhosis refers to intermediate or advanced cirrhosis, usually of Child-Pugh B or C grade. Patients have had serious complications such as ruptured bleeding from esophagogastric fundic varices, hepatic encephalopathy and ascites. Most of them have obvious manifestations of liver failure, such as serum albumin <35g/L, bilirubin >35μmol/L, ALT and AST are increased to different degrees, and prothrombin activity is mostly reduced (105 copies/ml in decompensated stage), they should be mobilized to do liver aspiration examination for further diagnosis and corresponding treatment. 3, inactive HBsAg carrier Serum HBsAg positive, HBeAg negative, anti-HBe positive or negative, HBV DNA undetectable (PCR method) or below the threshold, more than 3 consecutive follow-ups within 1 year, ALT are in the normal range. Histological examination of the liver shows that Knodell (Hepatitis Activity Index) HAI <4 or other semi-quantitative scoring system lesions are mild. (iv) Occult chronic hepatitis B Serum HBsAg negative, but HBV DNA positive in serum and/or liver tissue with clinical manifestations of chronic hepatitis B. Patients may be accompanied by positive serum anti-HBs, anti-HBe and/or anti-HBc; the other approximately 20% of patients with occult chronic hepatitis B are negative for HBV serologic markers except for HBV DNA positivity. The diagnosis needs to exclude other viral and non-viral factors causing liver injury. Laboratory tests (a) Biochemical tests 1, ALT and AST Serum ALT and AST levels can generally reflect the degree of liver cell damage, and are most commonly used. 2.Bilirubin Usually, serum bilirubin level is related to the degree of hepatocyte necrosis, but it should be distinguished from the elevated bilirubin caused by intrahepatic and extrahepatic bile stasis. Serum bilirubin is often higher in patients with liver failure and is progressively elevated (≥17.1 μmol/L per day), and may exceed 171 μmol/L. Bilirubin may also be separated from ALT and AST. 3, prothrombin time and prothrombin activity Prothrombin time (PT) is an important indicator of liver coagulation factor synthesis, and prothrombin activity (PTA) is a common method of PT measurement, which is of great value in determining disease progression and prognosis. It is also useful to express this index by international normalized ratio (INR). 4.Cholinesterase (ChE) reflects the synthetic function of the liver and can be used to determine the severity of the disease and monitor the development trend of liver disease. 5.Serum albumin reflects the synthetic function of the liver. In patients with chronic hepatitis B, cirrhosis and liver failure, serum albumin decreases or globulin increases, as shown by a decrease in the serum albumin/globulin ratio. 6. Significant elevation of alpha-fetoprotein (AFP) often indicates HCC, and mild elevation of AFP also often indicates regeneration of hepatocytes after massive hepatocyte necrosis, which may help to judge the prognosis and also monitor the occurrence of HCC, but attention should be paid to the magnitude and duration of AFP elevation and its dynamic changes, and combined with the patient's clinical manifestations and imaging findings such as B ultrasound for comprehensive analysis. (B) HBV serological testing HBV serological markers include HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc and anti-HBc Ig M. Currently, enzyme immunoassay (EIA), radioimmunoassay (RIA), microparticle enzyme immunoassay (MEIA) or chemiluminescence assay are often used for testing. is a protective antibody, and its positivity indicates immunity to HBV, which can be seen in hepatitis B recovery and hepatitis B vaccination; HBsAg turns negative while anti-HBs turns positive, which is called HBsAg seroconversion; HBeAg positivity can be used as an indicator of high HBV replication and infectivity; anti-HBe positive indicates low HBV replication level (except for those with pre-C region mutation); HBeAg turns negative while anti-HBe turns positive, which is called HBeAg seroconversion. Anti-HBeAg turns positive, called HBeAg seroconversion; anti-HBc IgM positive indicates HBV replication, mostly seen in the acute phase of hepatitis B; anti-HBc total antibody is mainly anti-HBc IgG, as long as the infection has been HBV, regardless of whether the virus is cleared, this antibody is positive. To understand whether there is HBV and hepatitis D virus (HDV) co-infection or overlap, HDAg, anti-HDV, anti-HDV IgM and HDV RNA can be measured. (iii) HBV DNA, genotype and variant testing 1. levels, and antiviral efficacy. 2, HBV genotyping Commonly used methods include: (1) genotype-specific primer PCR method; (2) restriction fragment length polymorphism analysis (RFLP); (3) linear probe reverse hybridization (INNO-LiPA); (4) PCR microplate nucleic acid hybridization enzyme immunoassay; (5) gene sequence determination method. However, there is no HBV genotyping kit officially approved by SFDA in China. 3, HBV drug-resistant mutant detection [33, 34] commonly used methods are: (1) HBV polymerase region gene sequence analysis; (2) restriction fragment length polymorphism analysis (RFLP); (3) fluorescence real-time PCR LightCycler method; (4) linear probe reverse hybridization method. The above methods have their advantages and disadvantages, and there is no unified standard or recognized best kit. The histopathological characteristics of chronic hepatitis B are: obvious inflammation of the confluent area, infiltrating inflammatory cells are mainly lymphocytes, a few plasma cells and macrophages; inflammatory cell aggregation often causes the confluent area to expand, and can destroy the boundary plate to cause interface hepatitis (interface hepatitis ), also known as piecemeal necrosis (piecemeal necrosis). necrosis). Inflammation of the confluent zone and its interface hepatitis are the characteristic lesions of chronic hepatitis B disease activity and progression. Hepatocyte degeneration and necrosis in the lobules, including fusion necrosis and bridging necrosis, become more pronounced as the lesion worsens. Inflammatory necrosis of hepatocytes, inflammation of the confluent area and interface can lead to excessive collagen deposition in the liver, liver fibrosis and fibrous septum formation. If further aggravated, it may lead to structural disorders of liver lobules, formation of pseudobullets and progression to cirrhosis. Immunohistochemical tests can show the presence or absence of HBsAg and HBcAg expression in hepatocytes; HBsAg cytoplasmic diffuse and cytosolic types, and HBcAg plasma and cytosolic expression suggest active HBV replication; HBsAg inclusion body and peripheral types and HBcAg nuclear expression suggest the presence of HBV in hepatocytes. Grading of liver tissue inflammation and necrosis in chronic hepatitis B (G), fibrosis staging (S) of the degree of fibrosis, can be referred to the 2001 Viral Hepatitis Control Program [32]. The Knodell HAI scoring system is commonly used internationally, and scoring systems such as Ishak, Scheuer and Chevallier or semi-quantitative scoring schemes can also be used to understand the degree of liver inflammatory necrosis and fibrosis, as well as to evaluate the efficacy of drugs [35-38]. VIII. Diagnostic imaging Ultrasound, CT and magnetic resonance imaging (MRI) of the liver, gallbladder and spleen can be performed. The main purpose of imaging examinations is to differentially diagnose and monitor the progression of chronic hepatitis B and to detect occupying lesions of the liver such as HCC. The overall treatment goal of chronic hepatitis B is to maximize the long-term suppression or elimination of HBV, reduce inflammatory necrosis and liver fibrosis, delay and stop disease progression, reduce and prevent liver decompensation, cirrhosis, HCC and its complications, thus improving the quality of life and prolonging survival time. Chronic hepatitis B treatment mainly includes antiviral, immunomodulatory, anti-inflammatory and hepatoprotective, anti-fibrotic and symptomatic treatment, among which antiviral treatment is the key, and standardized antiviral treatment should be performed as long as there is an indication and conditions allow.