Indications for antiviral therapy for hepatitis B include: (1) HBV DNA > 105 copies/ml; (> 104 copies/ml for HBeAg negative); (2) ALT at 2 to 10 times the upper limit of normal; (3) if ALT is within 2 times the upper limit of normal, a recent history of recurrent abnormal ALT is required; (4) in the case of overlapping fatty liver, drug or alcoholic liver disease, attention should be paid to exclude the above (5) If ALT is temporarily normal or low after short-term application of enzyme-lowering drugs, antiviral therapy should still be considered.
Commonly used drugs for antiviral therapy:
I. Interferon:
1, the classification of interferon:
There are three types of interferon, α, γ. INFα is an effective antiviral drug, including ordinary INFα, compound IFN and pegylated interferon (PEG- IFN a) that is, long-acting interferon.
The INFα commonly used clinically are type 2b (e.g. Anfolon, Kain IFN, Andafin, Interferon), type 1b (e.g. Seroquin, Yundein), type α2a (e.g. Intefin, Rohypnol), compound α subtype (Dry Fuzin), pegylated interferon (Pyroxin pegasys, Pegintron), domestic ordinary interferon price is lower than imported interferon, also can achieve The price of domestic ordinary interferon is lower than that of imported interferon, and can also achieve better efficacy, which can be accepted by domestic patients. The imported long-acting interferon can be injected once a week to effectively maintain the blood concentration, which can reduce the pain of injection and better efficacy than ordinary interferon, but the price is more expensive.
2, interferon absolute contraindications.
(1) allergic to interferon products.
(2) serious liver injury, including severe hepatitis, decompensated cirrhosis, etc.
(3) Severe thrombocytopenia, less than 30-50×109/L; leukopenia, less than 2.0-3.0×109/L, neutrophil count less than 1.0 × 109/L before treatment.
(4) History of psychiatric disorders (e.g., depression).
(5) Frequent seizures.
(6) Unabstinent alcohol/drug abusers and abstinent alcohol/drug abusers with a history of relapse.
(7) Uncontrolled or unstable autoimmune diseases such as thyroiditis, hyperthyroidism, etc.
(8) Those with a history of angina pectoris, myocardial infarction, and other serious cardiovascular disease.
(9) Pregnancy.
3. Tests to be done during treatment.
(1) routine blood tests should be performed every 1 to 2 weeks in the first month after the start of treatment, once every month thereafter, and once every 2 months after 6 months until the end of treatment; (2) biochemical indicators, including ALT, AST, etc., should be checked every 2 weeks for 3 times in the first month after the start of treatment, and once every 1 to 2 months thereafter; (3) virological markers: HBV DNA should be tested every 2 months after the start of treatment (3) virological markers: HBV DNA is detected once every 2 months after the start of treatment, HBV DNA is detected once every 3 months after 4 months, HBsAg, HBeAg, anti-Hbe can be detected once every 3-6 months; (4) thyroid function, blood sugar, renal function and urinary routine are detected once every 3 months; (5) special indicators of cautious users are closely observed, such as changes in blood sugar or changes in mental status.
4, the main adverse reactions of interferon and treatment.
(1) flu-like syndrome: very common, manifested as fever, chills, headache, muscle aches, weakness, etc., can be injected at bedtime IFN a, or in the injection of IFN a while taking antipyretic and analgesic drugs, such symptoms generally in 1 week after the gradual reduction or disappearance. For more sensitive patients, a small dose can be started and gradually increased to the therapeutic amount, which can significantly reduce the flu-like symptoms.
(2) Bone marrow suppression: mainly manifested as peripheral blood leukocyte and platelet reduction. If the absolute number of neutrophils <1.0×109/L and platelets <40×109/L, the dose of IFNα should be reduced; at the same time, leukostimulants such as leukostimulants or lysine should be used. 1 week later, if there is obvious improvement, the dose should be gradually increased, and the minimum effective amount should be 3MIU (every other day). If the absolute neutrophil count is <0.8×109/L and platelet count is <30×109/L, the drug should be stopped.
(3) Psychiatric abnormalities: may manifest as depression, paranoia, severe anxiety and psychosis. Therefore, the patient’s psychiatric condition should be assessed before using IFN a and closely observed during treatment. However, the drug should be discontinued promptly for those with obvious symptoms.
(4) IFN a can induce the production of autoantibodies: including anti-nuclear antibodies and anti-insulin antibodies. Clinical manifestations of corresponding diseases may occur and should be discontinued.
(5) Other rare adverse reactions: including cardiovascular complications (arrhythmia, ischemic heart disease, etc.), retinopathy, allergic reactions, etc. Interferon therapy should be discontinued.
Second, lamivudine (Herceptin).
Lamivudine is a nucleoside antiviral drug, which mainly acts on the DNA polymutase of hepatitis B virus, thus inhibiting DNA synthesis and viral replication. Routine dosage: 100 mg/tablet, orally, once daily. The drug can significantly inhibit HBV DNA levels, and the rate of HBeAg negative and anti-HBe positive conversion (called: HbeAg seroconversion) can be increased with the duration of treatment. Those with high pre-treatment ALT levels generally also have higher HBeAg seroconversion rates. Long-term treatment can reduce inflammation and decrease the incidence of liver fibrosis and cirrhosis, and patients with decompensated cirrhosis taking this drug can also improve liver function and prolong survival. In addition, lamivudine should be used in preoperative and postoperative liver transplant patients. It is not recommended for those with persistently normal liver function. The physician should explain the use of the drug to the patient before administration, and it should not be applied to those who cannot cooperate with adherence to the drug.
1. Contraindications.
(1) Allergic to the drug.
(2) Pregnant and lactating women.
(3) Renal insufficiency.
2. Precautions.
(1) YMDD mutation (drug resistance).
Often occurs due to drug induction. When YMDD mutation can be found in the original negative HBV DNA positive again or the original decline in DNA viral load, or ALT elevation as an indicator of disease progression, and occasionally cause liver function failure. The incidence of YMDD mutation has been reported to increase with the duration of drug use, with 14%, 38%, 49% and 66% at years 1, 2, 3 and 4, respectively. After the mutation of the virus, the treatment can be adjusted to adefovir, entecavir, interferon or other antiviral drugs according to the patient’s liver disease and viral replication status. It should be noted that the newly selected drugs need to be applied simultaneously with lamivudine for 2-3 months before discontinuing lamivudine to avoid aggravation of relapse after discontinuation.
(2) Discontinuation time.
Lamivudine course is generally more than one year, and a small number of patients such as cirrhosis need long-term application. Since lamivudine may rebound within 1-3 months or even half a year after discontinuation, HBV DNA may become positive again or DNA load may rise, or even the disease may become more serious than before treatment and dangerous. Therefore, it is important to provide pre-treatment awareness education for every patient who chooses lamivudine treatment, so that the patient can truly understand the dangers of stopping the drug at will and consider the time of stopping the drug under the guidance of the physician. Once there is a rebound condition aggravated by discontinuation of the drug, appropriate treatment measures should be taken immediately.
Third, adefovir.
Adefovir is a new drug used in China’s clinical practice in recent years, a synthetic nucleoside analogue, whose mechanism of action is to inhibit HBV DNA polymutase activity, thereby inhibiting HBVDNA replication. There is no cross-resistance with lamivudine, and it is effective in both compensated and decompensated cirrhosis patients with lamivudine resistance variants. Routine dosage: 10 mg/tablet, orally, once daily. Compared with lamivudine, its antiviral efficiency is lower, but the incidence of drug-resistant mutations is also lower.
1. Contraindications: Patients with proven hypersensitivity to any of its constituents.
2, adverse reactions: common adverse reactions in foreign clinical studies are headache, abdominal pain, nausea, gastrointestinal distension, diarrhea, etc. Adverse reactions in domestic clinical studies are mainly leukopenia (mild), diarrhea (mild) and hair loss (moderate). Mild elevation of serum creatinine occurs in about 2.5% of patients at therapeutic doses, and dose reduction is required for those with reduced renal function.
3.Application range.
(1) Lamivudine is applied after mutation.
(2) Because it is effective against both wild strains and lamivudine-resistant strains of hepatitis B virus, it can also be used as a first-line drug for those who are not using other antiviral drugs or those who have poor efficacy of other antiviral drugs, and there are several studies exploring its efficacy for hepatitis B alone.
(3) For patients with hepatitis B decompensated liver disease or liver transplantation.
IV. Entecavir.
Entecavir is a cyclic valeryl guanosine analogue, which is a highly effective, selective anti-HBV drug with better HBV inhibition and efficacy than lamivudine. No resistance variants were found in patients who were initially treated with entecavir, but patients who were resistant to lamivudine also had partial cross-resistance to entecavir, and thus had to be given at higher doses.
China’s SFDA has also approved it for the treatment of patients with chronic hepatitis B, but it is more expensive than lamivudine. Entecavir is available in two doses, 0.5 mg/tablet and 1.0 mg/tablet.
1. Contraindications: Patients with proven hypersensitivity to entecavir.
2, adverse reactions: well tolerated, mild to moderate adverse reactions, the most common adverse reactions are: headache, fatigue, dizziness, nausea, etc.
3.Application scope: (1) Patients with HBVDNA-positive and HBeAg-positive or negative chronic hepatitis B. Routine dosage: 0.5 mg/tablet, orally, once daily. (2) Patients with chronic hepatitis B who have failed lamivudine treatment (including YMDD variants), 1.0 mg/tablet, orally, once daily. Clinical studies have shown that increasing the dose to 1 mg/day in patients with YMDD mutations can effectively inhibit HBV DNA replication.