I. Pathologic diagnosis.
The purpose of liver tissue biopsy is to assess the extent of liver lesions in patients with chronic hepatitis B, to exclude other liver diseases, to determine prognosis and to monitor treatment response.
The pathology of chronic hepatitis B is characterized by marked inflammation in and around the confluent area, with infiltrating inflammatory cells, mainly lymphocytes and, to a lesser extent, plasma cells and macrophages; inflammatory cell aggregation often causes enlargement of the confluent area and can disrupt the border plate, causing interface hepatitis, also known as piecemeal necrosis. Degeneration and necrosis of hepatocytes in the lobules, including fusion necrosis and bridging necrosis, may also be seen, becoming more pronounced as the lesion worsens. Inflammatory necrosis of the liver can lead to excessive collagen deposition in the liver and formation of fibrous septa. If the lesion is further aggravated, it can cause structural disorder of liver lobules, pseudobullet formation and eventually progress to cirrhosis. The histological diagnosis of chronic hepatitis B includes pathogenesis, inflammatory necrosis activity and the degree of liver fibrosis. The grading of inflammatory necrosis of liver tissue (G1~4), the staging of the degree of fibrosis (S1~4).
Second, the overall goal of treatment.
The overall goal of chronic hepatitis B treatment is to maximize long-term suppression of HBV, reduce inflammatory necrosis of hepatocytes and liver fibrosis, delay and reduce the occurrence of liver failure, cirrhosis, HCC and its complications, thus improving quality of life and prolonging survival time.
Chronic hepatitis B treatment mainly includes antiviral, immunomodulatory, anti-inflammatory and antioxidant, anti-fibrotic and symptomatic treatment, among which antiviral treatment is the key, and standardized antiviral treatment should be carried out as long as there are indications and conditions allow.
Third, the general indications for antiviral therapy.
General indications include: (1), HBeAg positive, HBV DNA ≥ 105 copies/m l (equivalent to 2000 IU/mL); HBeAg negative, HBV DNA ≥ 104 copies/m l (equivalent to 2000 IU/mL); (2), ALT ≥ 2 × ULN; if treated with interferon, ALT should be ≤ 10 × ULN, total serum bilirubin should be <2 × ULN; (3), ALT <2 × ULN, but liver histology shows Knodell HAI ≥4, or inflammatory necrosis ≥G2, or fibrosis ≥S2.
Antiviral therapy should also be considered for those who are persistently HBV DNA positive and do not meet the above treatment criteria, but have one of the following conditions (1), for those with ALT > upper limit of normal and age > 40 years (III).
(2), For those with persistently normal ALT but older (>40 years old), close follow-up should be performed, preferably with liver biopsy; if liver histology shows Knodell HAI ≥4, or inflammatory necrosis ≥G2, or fibrosis ≥S2, antiviral therapy should be actively given (II).
(3) If dynamic observation reveals evidence of disease progression (e.g., enlarged spleen), liver histology is recommended, and antiviral therapy should be given if necessary (III).
Elevated ALT caused by drugs, alcohol or other factors should be excluded before starting treatment, as well as temporary normalization of ALT after application of enzyme-lowering drugs. In some special diseases such as cirrhosis or taking biphenyl structure derivatives, the AST level may be higher than ALT, and the AST level can be used as the main indicator at this time.
Fourth, interferon therapy.
China has approved the use of ordinary interferon a (2a, 2b and 1b) and pegylated interferon a (2a and 2b) for the treatment of chronic hepatitis B.
A meta-analysis showed that patients with chronic hepatitis B treated with plain interferon had better HBeAg seroconversion rates, HBsAg clearance rates, cirrhosis incidence, and HCC incidence than those without interferon therapy [49]. Four randomized controlled trials in HBeAg-negative patients showed response rates of 38% to 90% at the end of treatment, but durable response rates of only 10% to 47% (mean 24%) (I). It has been suggested that a course of at least 1 year of treatment with common IFN-a is necessary to achieve a good outcome (II).
International multicenter randomized controlled clinical trials have shown that HBeAg-positive patients with chronic hepatitis B treated with pegylated interferon a-2a (PegIFN-a2a) (87% Asian) for 48 weeks had a HBeAg seroconversion rate of 32% at 24 weeks of discontinuation follow-up; HBeAg seroconversion rates of up to 43% at 48 weeks of discontinuation follow-up. Foreign studies have shown that similar rates of HBVDNA suppression, HBeAg seroconversion, and HBsAg disappearance can be achieved with pegylated interferon a-2b (PegIFN-a2b) in HBeAg-positive chronic hepatitis B.
In HBeAg-negative chronic hepatitis B patients (60% Asian) treated with PegIFN-a2a for 48 weeks, the rate of HBV DNA <2?104 copies/mL (equivalent to 2000 IU/mL) was 43% at 24 weeks post-discontinuation and 42% at 48 weeks post-discontinuation; the HBsAg disappearance rate was 3% at 24 weeks post-discontinuation and increased to 8% by 3 years post-discontinuation. The rate of HBsAg disappearance was 3% at 24 weeks of discontinuation and increased to 8% at 3 years of discontinuation.
(a), interferon antiviral efficacy predictors.
The following factors often lead to better outcomes: (1), high pre-treatment ALT levels; (2), HBV DNA < 2?108 copies/ml; [< 4?107 IU/mL] (3), female; (4), short duration of disease; (5), non-maternal-to-child transmission; (6), heavy inflammatory necrosis of liver tissue and mild fibrosis; (7), good compliance with treatment; (8), no HCV, HDV or HIV co-infection; (9), HBV genotype A; and (10), undetectable serum HBVDNA at 12 or 24 weeks of treatment (II). Among them, pretreatment ALT, HBV DNA level and HBV genotype are important predictors of efficacy.
Some studies have shown that quantitative detection of HBsAg levels or HBeAg levels during PEG IFN-a2a treatment is a better predictor of treatment response.
(b), monitoring and follow-up of interferon therapy Before treatment, the following should be checked: (1), biochemical indicators, including ALT, AST, bilirubin, albumin and renal function; (2), routine blood, urine, blood glucose and thyroid function; (3), virological markers, including baseline status or levels of HBsAg, HBeAg, anti-HBe and HBV DNA; (4), for middle-aged or older patients, electrocardiogram and blood pressure should be performed; (5), exclude autoimmune diseases; (6), urine human chorionic gonadotropin (HCG) test to exclude pregnancy.
During the course of treatment, the following should be checked: (1) routine blood tests should be performed every 1~2 weeks in the first month after the start of treatment, and then once a month until the end of treatment; (2) biochemical indicators, including ALT and AST, should be performed once a month for 3 consecutive times after the start of treatment, and then once every 3 months as the disease improves; (3) virological markers should be tested once every 3 months after the start of treatment HBsAg, HBeAg, anti-HBe and HBV DNA; (4), others, thyroid function, blood glucose and urinary routine every 3 months; if thyroid function abnormalities exist before treatment or those who already have diabetes, thyroid function abnormalities or diabetes should be controlled with drugs before starting interferon treatment, and thyroid function and blood glucose levels should be checked monthly; (5) (ii) the patient should be regularly evaluated for mental status, and the medication should be immediately discontinued and closely monitored for patients with significant depression and suicidal tendencies.
(3), adverse reactions to interferon and its treatment.
1, flu-like syndrome manifested as fever, chills, headache, muscle aches and weakness, etc., can be injected at bedtime IFN-a, or in the injection of interferon while taking antipyretic and analgesic drugs.
2, transient peripheral blood cytopenia mainly manifested as peripheral blood leukocytes (neutrophils) and platelet reduction. If the absolute neutrophil count ≤ 0.75×109/L and/or platelets < 50×109/L, the dose of IFN-α should be reduced; recheck after 1~2 weeks and gradually increase to the original amount if it recovers. If absolute neutrophil count ≤ 0.5×109/L and/or platelets < 30×109/L, the drug should be discontinued. For those with significantly lower neutrophils, treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) can be tried (III).
3. Psychiatric abnormalities may manifest as depression, delusions, severe anxiety and other psychiatric symptoms. For patients with severe symptoms, IFN-a should be discontinued promptly, and if necessary, further consultation with a neuropsychiatrist should be conducted.
4.Autoimmune disease Some patients may develop autoantibodies, only a small number of patients appear thyroid disease (hypothyroidism or hyperthyroidism), diabetes, thrombocytopenia, psoriasis, leukoplakia, rheumatoid arthritis and systemic lupus erythematosus-like syndrome, etc., should be consulted and treated by the relevant departments, and the drug should be discontinued in serious cases.
5, other rare adverse reactions including kidney damage (interstitial nephritis, nephrotic syndrome and acute renal failure, etc.), cardiovascular complications (arrhythmia, ischemic heart disease and cardiomyopathy, etc.), retinopathy, hearing loss and interstitial pneumonia, etc., should stop interferon treatment.
(iv) Contraindications to interferon therapy.
Absolute contraindications to interferon therapy include pregnancy, history of psychiatric disorders (e.g., major depression), uncontrolled epilepsy, uncontrolled alcohol/drug abuse, uncontrolled autoimmune disease, decompensated cirrhosis, and symptomatic heart disease.
Relative contraindications to interferon therapy include thyroid disease, retinopathy, psoriasis, previous history of depression, uncontrolled diabetes mellitus, hypertension, pretreatment neutrophil count <1.0 ? 109/L and/or platelet count <50 ? 109/L and total bilirubin >51 mmol/L (especially if indirect bilirubin is predominant.)