"Chronic Hepatitis B Primary Diagnosis and Treatment Guidelines (Practical Edition·2020)" released!

Introduction Hepatitis B virus (HBV) infection is the main cause of chronic liver diseases such as cirrhosis and liver cancer.

It is estimated that the current prevalence of hepatitis B surface antigen (HBsAg) in my country is 5% to 6%, and there are about 70 million cases of chronic HBV infection, of which 20 million to 30 million are chronic hepatitis B (CHB) patients.

Although the medical burden caused by HBV-related diseases is heavy, and the treatment of CHB is constantly developing, most HBV infected people are still aware of their own infection status, which has caused some patients to have advanced to the late stage of the disease when they seek medical treatment.

Therefore, the early screening, diagnosis and follow-up care management of CHB are the key links of prevention and treatment.

1.
Test (1) The test subjects are recommended to actively perform HBsAg on children who have not been immunized against hepatitis B and adults over 18 years of age during health examinations or medical activities that do not involve nursery school, school enrollment, or employment.
And hepatitis B surface antibody (anti-HBs) detection to achieve the purpose of early diagnosis, early treatment, and reduction of disease hazards.

(2) Detection method 1.
HBV serological detection: currently the preferred detection method for HBV infection.

HBV serological markers include HBsAg, anti-HBs, hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe), hepatitis B core antibody (anti-HBc) and anti-HBc IgM.

The clinical significance is shown in Table 1 and 2.

Table 1 Clinical significance of HBV serological markers Table 2 Combination analysis of clinical significance of HBV serological markers 2.
HBV DNA quantitative detection: mainly used to judge the level of HBV replication, for the selection of antiviral therapy indications and the judgment of curative effect.

HBV DNA quantification mostly uses real-time quantitative polymerase chain reaction, and its detection limit varies with reagents from different manufacturers.

3.
Biochemical examinations: including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serum bilirubin, routine testing of peripheral blood, alpha-fetoprotein (AFP), etc.

4.
Non-invasive diagnosis of liver fibrosis: mainly introduces 3 methods, AST and platelet ratio index (APRI), liver fibrosis 4-factor index (FIB-4) and transient elastography (TE), including APRI score, FIB- 4 Simple and easy to implement, it can be carried out in the community and used for the evaluation of liver fibrosis.
TE is suitable for examination in large hospitals due to equipment limitations.

5.
Imaging examination: The main purpose is to monitor the clinical disease progression of chronic HBV infection, including understanding the presence or absence of signs of liver cirrhosis and portal hypertension, discovering hepatic space-occupying lesions and identifying their nature, especially monitoring and diagnosing hepatocellular carcinoma (HCC).
), the size of liver cancer at the first diagnosis is closely related to the prognosis, and regular abdominal ultrasound is the most effective means to screen for early liver cancer.

It is recommended that CHB patients without liver cirrhosis should be reviewed every 6 months, and CHB patients with liver cirrhosis should be reviewed every 3 months.

Contrast-enhanced ultrasound can better identify the nature of the space.

(3) Testing strategy It is recommended that children who have not been immunized against hepatitis B and people over 18 years old who have not undergone HBV related examinations should be tested for HBsAg and anti-HBs during physical examination or clinical visits.
If HBsAg is positive, it indicates the presence of HBV infection.
, And further check HBeAg, anti-HBe, anti-HBc, anti-HBc IgM, HBV DNA, liver function and abdominal ultrasound.

The detection strategy is shown in Figure 1.

Figure 1 HBV detection strategy Note: a Not applicable to confirmed HBV infection or acute exacerbation of chronic hepatitis B or severe hepatitis manifestations.
2.
The diagnosis is based on the serological, virological, biochemical tests and other clinical and auxiliary tests of HBV infected persons.
As a result of the examination, clinically, chronic HBV infection can be divided into the following categories: 1.
Chronic HBV carrier status: also known as HBeAg positive chronic HBV infection. Most of them are young people who are positive for HBsAg, HBeAg, and HBV DNA in the immune tolerance phase.
They are followed up 3 times within a year, at least 3 months apart.
They all show that serum ALT and AST are in the normal range, and HBV DNA is usually in the normal range.
High level (>2×107 IU/ml), high serum HBsAg (usually >1×104 IU/ml), liver histology examination shows no obvious inflammatory necrosis or fibrosis.

2.
HBeAg-positive CHB: The patient is in the immune clearance period.

Serum HBsAg is positive, HBeAg is positive, HBV DNA is positive (usually >2×104 IU/ml), ALT is persistent or repeated abnormally, or liver histological examination has obvious inflammation, necrosis and/or fibrosis.

3.
Inactive HBsAg carrying status: also known as HBeAg-negative chronic HBV infection.

In the immune control period, serum HBsAg positive, HBeAg negative, anti-HBe positive or negative, HBV DNA<2×103 IU/ml, HBsAg<1×103 IU/ml, follow up more than 3 times in a year, at least every time At 3 months, both ALT and AST were in the normal range.

The imaging examination showed no signs of cirrhosis, and the liver histological examination showed that the histological activity index (HAI) score was less than 4 or the lesion was judged to be mild according to other semi-quantitative scoring systems.

4.
HBeAg negative CHB: it is the reactivation period.

Serum HBsAg is positive, HBeAg is persistently negative, HBV DNA is positive (usually ≥2×103 IU/ml), ALT is persistent or recurrent abnormal, or liver histology has hepatitis lesions.

5.
Occult HBV infection (OBI): It is defined as negative for serum HBsAg, but positive for HBV DNA in serum and/or liver tissue.

In addition to HBV DNA positive, 80% of patients may have serum anti-HBs, anti-HBe and/or anti-HBc positive, which is called seropositive OBI; 1%-20% of OBI patients have negative serological markers , Called serology negative OBI.

Diagnosis is mainly through HBV DNA testing, especially those who are persistently positive for anti-HBc.

The mechanism of its occurrence is not completely clear.

6.
Hepatitis B cirrhosis: If the diagnosis of hepatitis B cirrhosis meets the following (1) and (2), it is a pathological diagnosis, and those that meet (1) and (3) are a clinical diagnosis.

(1) Patients with current HBV infection (HBsAg positive) or a clear history of chronic HBV infection (previous HBsAg positive> 6 months, current HBsAg negative, anti-HBc positive) and other causes are excluded.

(2) The pathology of liver biopsy is consistent with the manifestations of liver cirrhosis.

(3) Those who meet 2 or more of the following 5 items, and exclude non-cirrhotic portal hypertension: ① The imaging examination shows signs of liver cirrhosis and/or portal hypertension.

②Endoscopy showed esophagus and gastric fundus varicose veins.

③The liver TE measurement showed that the liver stiffness was consistent with cirrhosis.

④ The blood biochemical examination showed that the albumin level was reduced (<35 g/L) and/or prothrombin time was prolonged (>3s longer than the control).

⑤ Routine examination of peripheral blood showed that the platelet count was less than 100×109/L, etc.

In clinical practice, liver cirrhosis is often divided into a compensatory phase and a decompensated phase based on whether there have been serious complications such as ascites, rupture of esophageal and gastric varices and hepatic encephalopathy.

Compensated liver cirrhosis refers to imaging, biochemical or hematological examinations with evidence of hepatocyte synthesis dysfunction or portal hypertension, or histology is consistent with the diagnosis of liver cirrhosis, but there is no esophageal gastric varices bleeding, ascites, or hepatic encephalopathy Such as symptoms or severe complications.

Decompensated liver cirrhosis refers to patients who have experienced one of serious complications such as rupture of esophageal and gastric varices, hepatic encephalopathy, and ascites.

3.
Treatment (1) Treatment goals: To maximize long-term inhibition of HBV replication, reduce inflammation and necrosis of liver cells and liver fibrosis, delay and reduce the occurrence of liver failure, decompensation of liver cirrhosis, HCC and other complications, thereby improving life Quality and prolong survival time. (2) Indications for antiviral therapy Antiviral therapy is currently mainly based on serum HBV DNA, ALT levels and the severity of liver disease, combined with factors such as age, family history, and concomitant diseases, to comprehensively assess the patient’s risk of disease progression and determine whether it is necessary Initiate antiviral treatment.

1.
CHB patients with positive serum HBV DNA: If the ALT continues to be abnormal (>1 times ULN) and other causes of ALT increase are excluded, antiviral therapy should be considered.

Other causes of elevated ALT include: infection by other pathogens, drug-induced liver injury, alcoholic hepatitis, steatohepatitis, autoimmune hepatitis, systemic diseases involving the liver and other factors.

At the same time, temporary normal ALT after the application of liver-protecting and enzyme-lowering drugs should also be excluded.

2.
Liver cirrhosis: For patients with compensated liver cirrhosis, no matter the ALT and HBeAg status, as long as the HBV DNA can be detected, active antiviral treatment is recommended.

For patients with decompensated liver cirrhosis, as long as HBsAg positive, antiviral therapy is recommended.

3.
Those with positive serum HBV DNA and normal ALT have one of the following conditions, and the risk of disease progression is greater.
Antiviral therapy is recommended: (1) There is obvious liver inflammation (G2 and above) or liver fibrosis in liver histology ( S2 level and above).

(2) ALT continues to be normal (check once every 3 months for 12 months), have a family history of liver cirrhosis or liver cancer, and are older than 30 years old.

(3) ALT continues to be normal (check once every 3 months for 12 months), no family history of liver cirrhosis or liver cancer, age> 30 years old, it is recommended to perform non-invasive liver fibrosis examination or liver histological examination, there is obvious Those with liver inflammation or fibrosis.

(4) ALT continues to be normal (check once every 3 months for 12 months) and those with HBV-related extrahepatic manifestations (glomerulonephritis, vasculitis, polyarteritis nodosa, peripheral neuropathy, etc.
) . (3) Preliminary assessment of CHB patients before treatment 1.
Assessment of the severity of liver disease includes medical history, physical examination (whether there is hepatomegaly and splenomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, albumin) , Total bilirubin, complete blood count) and abdominal ultrasound.

2.
Conduct detailed consultations on liver-related symptoms, and evaluate the liver's synthetic function based on human albumin levels and prothrombin time or international normalized ratio (INR).

The level of virus replication was evaluated based on HBV DNA quantification.

3.
Evaluation of other comorbidities: including HIV, HCV or hepatitis D virus (HDV), impaired glucose tolerance, dyslipidemia, non-alcoholic fatty liver disease, alcoholic liver disease, iron overload, and drugs and toxins.
For liver injury, all patients with liver cirrhosis should be screened for HCC, and the family history and medication history of HCC should be understood.

4.
Taking into account the testing conditions and drug availability issues in remote areas of the country, such as the absence of HBV DNA, non-invasive liver fibrosis testing and other conditions, for patients with chronic HBV infection, such as persistent abnormal liver function and hepatitis symptoms, nucleosides may also be considered (Acid) analogs (NAs) treatment.

(4) Before preparing for treatment, consultation and advice should be provided to patients, including detailed explanations of treatment benefits and possible adverse reactions, follow-up monitoring intervals and inspection items during treatment and after stopping treatment, the necessity of long-term treatment, and treatment compliance The importance of sex for curative effect and reducing the risk of drug resistance, as well as the cost of long-term treatment monitoring that may cause viral and biochemical rebound or chronic acute liver failure if treatment is stopped suddenly.

(V) Antiviral therapy drugs 1.
The efficacy and safety of NAs drugs: Entecavir, tenofovir disoproxil fumarate, and tenofovir fumarate are the preferred NAs drugs, which can strongly inhibit virus replication , Improve liver inflammation, safety is good, and the overall drug resistance rate is low.
Long-term application can significantly reduce the incidence of liver cirrhosis complications and HCC, and reduce liver-related and all-cause mortality. NAs are generally safe and well tolerated, but there are rare and rare serious adverse reactions in clinical applications, such as renal insufficiency (taking adefovir dipivoxil or tenofovir disoproxil fumarate), low phosphorus Osteopathy (taking adefovir dipivoxil or tenofovir disoproxil fumarate), myositis or rhabdomyolysis (taking telbivudine or lamivudine), lactic acidosis, etc.
(taking entecavir and telbivudine) Set), should cause concern.

It is recommended to ask the relevant medical history carefully before treatment and evaluate the renal function to reduce the risk.

During the treatment, according to the needs of the disease, routine blood tests, serum creatinine and creatine kinase (CK), etc.
, can be tested regularly.
If necessary, blood phosphorus, lactic acid and renal tubular function can be tested.
If serum creatinine, CK or lactate dehydrogenase is significantly increased, Patients with corresponding clinical manifestations, such as general deterioration, obvious myalgia, muscle weakness, etc.
, should adjust the antiviral program in time and give active corresponding treatment intervention.

2.
Selection of NAs: The initial patients should be treated with strong and low-resistant drugs (entecavir, tenofovir disoproxil fumarate, tenofovir fumarate).

For patients who have been treated or are being treated with other drugs, it is recommended to switch to strong and low drug resistance drugs to further reduce the risk of drug resistance.

For patients treated with adefovir dipivoxil, it is recommended to switch to entecavir, tenofovir disoproxil fumarate, and tenofovir propofol fumarate; for patients who use lamivudine or telbivudine, it is recommended to switch to fumar Tenofovir disoproxil, propofol fumarate, tenofovir or entecavir; for those who have been resistant to lamivudine or telbivudine, switch to tenofovir disoproxil fumarate or propofol fumarate Tenofovir; For those who have been resistant to adefovir dipivoxil, switch to entecavir, tenofovir disoproxil fumarate, tenofovir propofol fumarate; combine adefovir dipivoxil and lamivudine Patients with telbivudine can switch to tenofovir disoproxil fumarate or tenofovir propofol fumarate.

3.
Interferon-α treatment: my country has approved peginterferon (Peg-IFN-α) and ordinary interferon (IFN-α) for the treatment of chronic hepatitis B.
The former only requires injection once a week.

As the treatment of interferon is more complicated, specialist treatment and management are recommended.

(6) Timing of stopping treatment 1.
Long-term NAs treatment: For patients with CHB liver cirrhosis, long-term use of entecavir, tenofovir disoproxil fumarate, and tenofovir fumarate antiviral therapy is recommended.

2.
Stop treatment: It is recommended to make a cautious decision after discussing with a specialist, and make a long-term and strict follow-up plan with the patient after stopping the drug.

3.
Retreatment: After stopping NAs treatment, there may be recurrence.
If there are signs of reactivation (HBsAg or HBeAg becomes positive, ALT level rises or HBV DNA becomes positive again), retreatment is recommended.

The above content is extracted from: Guidelines for Diagnosis and Treatment of Chronic Hepatitis B (Practical Edition·2020)[J].
Chinese Journal of General Practitioners, 2021, 20(03):281-289.
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