This guideline is intended to help physicians make rational decisions in the diagnosis and prevention of chronic hepatitis B. It is not a mandatory standard, nor can it include or address all issues in the diagnosis and treatment of chronic hepatitis B. Therefore, when faced with a particular patient, clinicians should develop a comprehensive and reasonable treatment plan based on their professional knowledge, clinical experience, and available medical resources, with full knowledge of the best clinical evidence about the disease and careful consideration of the patient’s specific condition and his or her wishes. We will continue to update and improve this guideline in accordance with the relevant advances at home and abroad.
I. Pathogenesis
Hepatitis B virus (HBV) belongs to the family of hepadnaviridae, with a genome length of about 3.2 kb and a part of double-stranded circular DNA. HBV is highly resistant, but HBV can be inactivated by 65℃ for 10 h, boiling for 10 min or high-pressure steam, and HBV can also be inactivated by ethylene oxide, glutaraldehyde, peroxyacetic acid and iodoform.
After HBV invades hepatocytes, part of the double-stranded cyclic HBV DNA is used in the nucleus to extend the positive chain with negative-stranded DNA as a template to repair the gap area in the positive chain, forming covalent closed-loop DNA (cccDNA); then cccDNA is used as a template to transcribe into several mRNAs of different lengths, which are used as pregenomic RNA and encode various antigens of HBV. (The cccDNA has a long half-life and is difficult to completely remove from the body.
HBV has been found to have nine genotypes from A to I [4, 5], with C and B types predominating in China. HBV genotype is associated with disease progression and the effect of interferon alpha therapy. Compared with those infected with genotype C, those infected with genotype B showed earlier HBeAg serological conversion and less progression to chronic hepatitis, cirrhosis and primary hepatocellular carcinoma [6-9]; and the response rate to interferon α therapy was higher in HBeAg-positive patients than in genotype C; and higher in genotype A than in genotype D.
II. Epidemiology
HBV infection is endemic worldwide, but the prevalence intensity of HBV infection 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 them are chronic HBV infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma (HCC) caused by HBV infection.
The 2006 national epidemiological survey of hepatitis B showed that the HBsAg carriage rate of the general population aged 1-59 in China was 7.18%, and that of children under 5 years old was only 0.96%. According to this projection, the existing chronic HBV infection in China is about 93 million people, including about 20 million cases of chronic hepatitis B patients.
HBV is a blood-borne disease, mainly through blood (such as unsafe injection, etc.), mother-to-child and sexual contact transmission, due to the implementation of strict HBsAg screening of blood donors, HBV infection caused by blood transfusion or blood products has been less frequent; transmission through broken skin mucous membranes is mainly due to the use of medical equipment not strictly sterilized, invasive diagnostic and surgical operations, unsafe injection, especially injection of drugs, etc.; Other infections such as foot trimming, tattooing, ear piercing, accidental exposure of medical personnel at work, sharing of razors and toothbrushes, etc. can also be transmitted.
Mother-to-child transmission occurs mainly during the perinatal (labor) period, mostly from contact with the blood and body fluids of HBV-positive mothers during delivery, but with the use of hepatitis B vaccine combined with hepatitis B immunoglobulin, mother-to-child transmission has been greatly reduced. The risk of HBV infection increases with unprotected sexual contact with HBV-positive people, especially those with multiple sexual partners.
HBV is not transmitted through the respiratory and digestive tracts, so daily study, work or living contacts, such as working in the same office (including sharing office supplies such as computers), shaking hands, hugging, living in the same dormitory, eating in the same restaurant and sharing toilets without blood exposure, generally do not transmit HBV. epidemiological and experimental studies have not found that HBV can be transmitted through blood-sucking insects (mosquitoes, bedbugs, etc.).
Natural history
Age at the time of infection is the most important factor affecting chronicity. Among those infected with HBV during the perinatal (birth) period and infancy, 90% and 25%-30%, respectively, will develop chronic infection, while only 5-10% of those infected after the age of 5 years will develop chronic infection. The natural history of HBV infection in infancy can generally be artificially divided into four phases, namely the immune tolerance phase, the immune clearance phase, the inactive or low (non) replication phase and the reactive phase.
Immunotolerant phase: characterized by positive serum HBsAg and HBeAg, high HBV DNA load ( often > 106 IU/mL, equivalent to 107 copies/mL), but normal serum alanine aminotransferase (ALT) levels, no significant abnormalities in liver histology that can be maintained for years or even decades [22], or mild inflammatory necrosis with no or only slow progression of liver fibrosis. Immunoclearance phase: manifested by serum HBV DNA titers > 2000 IU/mL (equivalent to 104 copies/mL) with persistent or intermittent elevation of ALT, moderate or severe inflammatory necrosis of liver histology, liver fibrosis may progress rapidly, and some patients may develop cirrhosis and liver failure.
Inactive or low (non) replication stage: manifested by HBeAg negative, anti-HBe positive, HBV DNA consistently below 2000 IU/mL (equivalent to 104 copies/mL) or undetectable (PCR method), normal ALT levels, and no or only mild inflammation of liver histology; this is the result of immune control of HBV infection, and most patients in this stage have cirrhosis and The risk of HCC is greatly reduced, and in some patients who have sustained HBV DNA conversion for several years, the spontaneous HBsAg serological conversion rate is 1 to 3%/year.
Reactive phase: Some patients in the inactive phase may have one or more episodes of hepatitis, mostly presenting as HBeAg negative, anti-HBe positive (partly due to low or no HBeAg expression levels caused by pre-C region and/or BCP variants), but still have active HBV DNA replication, persistent or recurrent abnormal ALT, and become HBeAg negative chronic hepatitis B. These patients may progress to liver fibrosis, cirrhosis, decompensated cirrhosis and HCC; some patients may also develop spontaneous HBsAg disappearance (with or without anti-HBs) and reduced or undetectable HBV DNA, thus the prognosis is often good.
A small number of patients at this stage can return to HBeAg-positive status (especially in immunosuppressed states such as when receiving chemotherapy).
Not all people infected with HBV go through these four stages. Only a minority (about 5%) of HBV infections in the neonatal period result in spontaneous clearance of HBV, while most have a long period of immune resistance and then enter the immune clearance phase. However, most HBV infections in adolescence and adulthood do not have an immune tolerance period but enter directly into the immune clearance phase, and most of them can clear HBV spontaneously (about 90%-95%), while a minority (about 5%-10%) develop HBeAg-positive chronic hepatitis B.
Spontaneous HBeAg serological conversion mainly occurs during the immune clearance period, with an annual incidence of about 2%-15%, with a higher incidence in those younger than 40 years old, with elevated ALT, and infected with HBV genotypes A and B. HBsAg clearance occurs in about 0.5%-1.0% per year after HBeAg serological conversion.
The incidence of cirrhosis in chronic HBV-infected patients is related to the infection status. Patients in the immune tolerance phase have only very mild or no progression of liver fibrosis, whereas the immune clearance phase is a period of high incidence of cirrhosis. The cumulative incidence of cirrhosis is positively correlated with persistently high viral load, and HBV DNA is a risk factor independent of HBeAg and ALT that can independently predict the development of cirrhosis. Risk factors for the development of cirrhosis also include alcoholism, co-infection with HCV, HDV or HIV.
Non-cirrhotic patients are less likely to develop primary hepatocellular liver cancer (HCC). HBeAg positivity and/or HBV DNA > 2,000 IU/mL (equivalent to 104 copies/mL) are significant risk factors for the development of cirrhosis and HCC. Large sample studies have shown that older age, male sex, and high ALT levels are also risk factors for the development of cirrhosis and HCC. family history of HCC is also a relevant factor, but HBV viral load is more important in the same genetic background.
(i) Hepatitis B vaccination prevention
Vaccination against hepatitis B is the most effective way to prevent HBV infection. The target population for hepatitis B vaccination is mainly newborns [37], followed by infants and children, unimmunized people under 15 years of age and high-risk groups (e.g., medical personnel, people with frequent exposure to blood, workers in child care institutions, organ transplant patients, frequent recipients of blood transfusions or blood products, immunocompromised people, people prone to trauma, family members of HBsAg-positive people, men who have sex with men or have multiple The hepatitis B vaccine should be administered to all patients (including those who have multiple sexual partners and those who inject drugs intravenously).
Three doses of hepatitis B vaccine are required for the entire course, according to the 0, 1, and 6 months procedure, i.e. after the first dose, the second and third doses are given at intervals of 1 month and 6 months. Hepatitis B vaccination for newborns should be given within 24 hours of birth, the earlier the better. The vaccination site is intramuscular in the lateral anterior gluteal muscle for newborns and intramuscular in the middle deltoid muscle of the upper arm for children and adults.
The blockage rate of mother-to-child transmission with hepatitis B vaccine alone was 87.8% [38] (II-3). In neonates of HBsAg-positive mothers, hepatitis B immunoglobulin (HBIG) at a dose of ≥100 IU should be administered as early as possible within 24 h after birth (preferably 12 h after birth), along with 10 μg of recombinant yeast or 20 μg of Chinese hamster oocyte (CHO) hepatitis B vaccine at different sites, and the second and third doses of hepatitis B at 1 and 6 months of age, respectively. The effectiveness of interruption of mother-to-child transmission is significantly improved by vaccination with hepatitis B vaccine at 1 and 6 months of age.
It is also possible to administer one dose of HBIG within 12 h of birth, followed by a second dose of HBIG 1 month later, and one 10 μg recombinant yeast or 20 μg CHO hepatitis B vaccine at different sites at the same time, with a second and third dose of hepatitis B vaccine at 1 and 6 months intervals, respectively [39]. Newborns were allowed to receive breastfeeding from HBsAg-positive mothers after HBIG and hepatitis B vaccine were administered within 12 h of birth (III).
Newborns of HBsAg-negative mothers can be immunized with 5 μg or 10 μg yeast or 10 μg CHO hepatitis B vaccine; children who were not vaccinated against hepatitis B during the neonatal period should be given a catch-up dose of 5 μg or 10 μg recombinant yeast or 10 μg CHO hepatitis B vaccine; for adults, 20 μg yeast or 20 μg CHO hepatitis B vaccine is recommended. For those who are immunocompromised or non-responders, the vaccination dose (e.g. 60 μg) and number of doses should be increased; for those who do not respond to the 3-dose immunization program, 3 more doses can be given, and the anti-HBs in the serum should be tested 1~2 months after the second 3-dose hepatitis B vaccine, and if there is still no response, a 60 μg recombinant yeast hepatitis B vaccine can be given.
The protective effect of hepatitis B vaccination for those with antibody response generally lasts for at least 12 years, therefore, anti-HBs monitoring or booster immunization is not required 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 (III).
(ii) Cut off the transmission route
Safe injection (including needles for acupuncture) is strongly promoted, and the principle of Standard Precaution in hospital infection management is strictly followed. Haircutting, shaving, pedicure, piercing and tattooing instruments used in the service industry should also be strictly disinfected. Pay attention to personal hygiene and do not share razors and dental equipment with anyone. Provide proper sex education. If the sexual partner is HBsAg positive, he/she should be vaccinated against hepatitis B or use condoms; always use condoms to prevent hepatitis B and other blood-borne or sexually transmitted diseases when the health status of the sexual partner is unknown. For HBsAg-positive pregnant women, avoid amniocentesis and shorten the delivery time to ensure the integrity of the placenta and minimize the exposure of the newborn to maternal blood.
(C) HBV prophylaxis after accidental exposure
After accidental exposure to the blood and body fluids of HBV-infected individuals, the following methods can be followed.
1, Serological testing should be performed immediately for HBV DNA, HBsAg, anti-HBs, HBeAg, anti-HBc, ALT and AST and reviewed within 3 and 6 months.
2. Active and passive immunization can be done without special treatment if hepatitis B vaccine has been administered and anti-HBs ≥10 mIU/mL is known. If you have not received hepatitis B vaccine, or have received hepatitis B vaccine but anti-HBs <10 mIU/mL or the level of anti-HBs is unknown, you should immediately inject HBIG 200-400 IU and receive a dose of hepatitis B vaccine g). mg) at different sites at the same time, and receive the second and third doses of hepatitis B vaccine (20 m) each after 1 and 6 months, respectively
(iv) Management of patients and carriers
When acute or chronic hepatitis B is diagnosed, it should be reported to the local disease prevention and control center as required, and it is recommended that family members of the patient be tested for serum HBsAg, anti-HBc and anti-HBs, and that those who are susceptible (those who are negative for these three markers) be vaccinated against hepatitis B.
The infectivity of hepatitis B patients and carriers depends mainly on the level of HBV DNA in the blood, but not on serum ALT, AST or bilirubin levels. Follow-up of patients and carriers of hepatitis B is described in this guideline under “Patient Follow-up”.
For chronic HBV carriers and HBsAg carriers (see “Clinical diagnosis” in this guideline)