Patients with HBV-associated liver failure HBV infection is one of the leading causes of liver failure in China. HBV-associated liver failure can be further classified as acute liver failure, subacute liver failure, slow-plus-acute liver failure and chronic liver failure. Nucleoside (acid) analogs can be safely used in the treatment of HBV-associated liver failure and can improve the prognosis of patients. The use of nucleoside (acid) analogs in patients with HBV-related acute and subacute liver failure may improve their survival and reduce the incidence of complications associated with liver failure. Early antiviral treatment with nucleoside (acid) analogs should be considered for patients with HBsAg-positive or HBV DNA-positive acute and subacute liver failure. For such patients, it is recommended to apply LAM, ETV and LdT nucleoside (acid) analogues with rapid viral inhibition, and long-term application should be monitored for the occurrence of drug resistance. The presence of HBsAg and HBV DNA below the lower limit of detection during the antiviral process does not completely exclude that HBV remains in the body, so antiviral therapy should be continued until HBsAg serological conversion occurs. Patients who are anti-HBs positive at the time of consultation do not need to be treated with antiviral therapy. Plasma HBV DNA load correlates with the prognosis of chronic plus acute and chronic liver failure, with a poorer prognosis in those with high viral load [8]. Antiviral treatment with nucleoside (acid) analogs in patients with chronic acute and chronic liver failure may improve the patient’s condition, increase survival and reduce the risk of hepatitis B recurrence after liver transplantation. For patients with early or mid-stage HBV-related chronic plus acute liver failure, antiviral therapy can be considered if HBV DNA is positive; patients with advanced chronic plus acute liver failure and chronic liver failure often require liver transplantation and should be treated with antiviral therapy as long as HBsAg or HBV DNA is positive. Patients who have not previously been treated with nucleoside (acid) analogs may be considered for LAM, ETV and LdT nucleoside (acid) analogs with rapid viral inhibition. For slow-onset acute liver failure due to hepatitis relapse after discontinuation of nucleoside analogs, the original antiviral drug can be used or replaced by other nucleoside analogs (III). Chronic plus acute liver failure due to viral mutation during nucleoside (acid) analogue therapy should be treated as early as possible with a nucleoside (acid) analogue that is not cross-resistant to the previous drug. HBV-associated liver transplant patients Patients presenting with HBV-associated end-stage liver disease or liver cancer awaiting liver transplantation should be treated with nucleoside (acid) analogs with strong HBV inhibition and low incidence of drug resistance, or with a combination of nucleoside (acid) analogs to obtain the lowest possible viral load and to prevent reinfection of the transplanted liver. LAM and/or ADV in combination with hepatitis B immunoglobulin (HBIG) can safely and effectively prevent reinfection of the transplanted liver. This regimen can reduce the rate of reinfection of the transplanted liver to less than 10% [10]. The addition of ADV is recommended for patients who develop resistance after LAM application. Evidence for the use of nucleoside (acid) analogues with strong HBV inhibition and low resistance rates, such as ETV and tenofovir (TDF), for the prevention of reinfection of the transplanted liver is insufficient. HBV-associated liver transplant patients require lifelong antiviral medication to prevent hepatitis B recurrence. HBsAg-negative patients should also receive long-term LAM or hepatitis B immunoglobulin prophylaxis when receiving an anti-HBc-positive individual donor liver. Patients with primary hepatocellular carcinoma HBV infection plays an important role in the occurrence of Chinese patients with hepatocellular carcinoma, and most of them have a cirrhotic base, so their antiviral treatment should be integrated with the patient’s ALT, HBV DNA, cirrhotic compensations and renal function to decide the treatment plan. For patients with hepatocellular carcinoma with HBV infection, surgical resection or radiofrequency ablation treatment may lead to active HBV replication and aggravate liver function damage, so antiviral therapy can be selected depending on liver function compensation. IFN α can achieve both antiviral and antitumor effects, delay tumor recurrence and prolong patients’ median survival. If patients can tolerate IFN α therapy, IFN α antiviral therapy should be preferred. If patients have contraindications to IFN α application, nucleoside (acid) analogues such as LAM, ADV, ETV and LdT can be selected according to the patient’s HBV DNA load, cirrhosis compensation and renal function. For patients with stable liver function who receive hepatic artery infusion chemotherapy, nucleoside (acid) analogs should be given prophylactically before the start of chemotherapy in order to prevent the activation of HBV DNA and consequent damage to liver function due to chemotherapy (see the section below on patients treated with chemotherapy and immunosuppression). Patients with advanced hepatocellular carcinoma, embolization of major branches of the portal vein, and no contraindications to IFN alpha may benefit from the administration of arterial infusion chemotherapy in combination with IFN alpha to prolong patient survival. Elderly patients with chronic hepatitis B Referring to the World Health Organization criteria, elderly patients with chronic hepatitis B are defined as those aged ≥ 60 years. In general, the treatment of elderly patients can refer to the general treatment plan for patients with chronic hepatitis B. Age should not be a contraindication to antiviral therapy for chronic hepatitis B. However, the following issues should be noted in elderly patients: 1. The treatment of elderly patients should be a comprehensive assessment of the patient’s willingness to treat, the risk of treatment, and the benefit of treatment. In particular, patients treated with IFN α should be comprehensively evaluated for expected survival, liver function compensation, tolerance to possible adverse effects, underlying diseases such as combined hypertension, diabetes, coronary artery disease, and possible improvement of liver function after treatment. 2. Patients should be closely monitored for treatment response and adverse reactions during and after treatment, and attention should also be paid to monitoring patients’ blood glucose, renal function and the occurrence of hepatocellular carcinoma. Pediatric patients Most pediatric patients with chronic HBV infection are in the immune tolerance period of HBV infection and may not be treated with antiviral therapy for the time being, but must be followed up and observed regularly. Currently the FDA approved drugs for pediatric patients include generic IFN alpha (2 to 17 years old), LAM (2 to 17 years old) and ADV (12 to 17 years old). Clinical trials have shown that the efficacy of IFN alpha in pediatric patients is comparable to that of adult patients. The recommended dose of IFN alpha for pediatric patients is 6 MIU/m2 body surface area three times per week, up to a maximum of 10 MIU/m2 body surface area per dose. clinical trials of LAM in pediatric patients have shown that LAM safely and effectively inhibits HBV DNA and increases the rate of HBeAg seroconversion in patients, but the rates of LAM resistance are 19%, 49% and 64% for 1-3 years of treatment, respectively. The dose of LAM for pediatric patients is 3 mg/(kg・d) and the maximum dose is 100 mg/d. The recommended dose and usage of ADV for pediatric patients aged 12 to 17 years is the same as that for adult patients. However, due to the young age of pediatric patients and the small number of drugs available for treatment, the indications for treatment should be strict. For children aged 2 to 11 years, antiviral therapy with common IFN and LAM should be administered with adequate communication and informed consent from parents. Combined ADV can be considered when drug-resistant variants occur in patients over 12 years of age applying LAM. Pregnant patients Mother-to-child transmission of HBV is the main transmission route of HBV infection in China [19], and antiviral therapy for pregnant patients is particularly important, and due to the special nature of pregnancy, their antiviral therapy should pay attention to the following issues: 1. Antiviral therapy should be completed before pregnancy as much as possible: chronic hepatitis B in pregnant Patients in pregnancy with chronic hepatitis B antiviral therapy to consider the safety of antiviral drugs in pregnancy this challenge, therefore, patients with fertility requirements should try to carry out effective antiviral therapy before pregnancy, with a view to completing antiviral therapy in the first 6 months of pregnancy. IFN has pregnancy toxicity, and patients with unintended pregnancy during antiviral therapy with IFN need to terminate the pregnancy. Although none of the available nucleoside (acid) analogs have been clinically tested in pregnant patients, numerous studies have demonstrated the safety of LAM and TDF (which are not currently available in China) in pregnant patients. Patients with unplanned pregnancy during antiviral therapy with LAM can continue LAM antiviral therapy with adequate communication with the patient. Patients treated with LdT, ADV and ETV antiviral therapy may be considered to switch to LAM to continue antiviral therapy. 3. Antiviral treatment for patients with hepatitis attacks during pregnancy: Pregnant patients with mildly elevated ALT can be closely observed or given temporary liver-protective symptomatic treatment, and then antiviral treatment can be given after delivery. Pregnant patients with more severe liver lesions may be considered for antiviral therapy after full consultation with the patient and signing of informed consent, and LAM may be applied for antiviral therapy. 4, mother-to-child transmission blockade of HBV infection: In children with failed mother-to-child transmission blockade, about 90% of the children have HBeAg-positive mothers. Serum HBV DNA load in pregnant patients is one of the key factors of mother-to-child transmission, and effective antiviral therapy can significantly reduce the incidence of mother-to-child transmission of HBV. A study showed [20] that LAM antiviral therapy given after 34 weeks of gestation had similar adverse effects in the drug and control groups, but at 1 year of age, the infant HBsAg detection rate was 18% in the drug group compared to 39% in the control group. Another study of LdT for mother-to-child transmission interruption showed that. Oral administration of LdT 600 mg/d at 28 to 32 weeks of gestation significantly reduced HBV DNA load before delivery and reduced infant HBsAg positivity at 7 months compared with the unmedicated group (0% vs 13.3%, P < 0.05). Therefore, based on the available evidence, maternal-to-child transmission blockade with LAM or LdT can be performed at 28 to 34 weeks of gestation. The discontinuation regimen for patients at the end of pregnancy can be referred to the discontinuation regimen for patients applying immunosuppression or chemotherapy below. 5. Fertility in male patients on antiviral therapy: Male patients on IFN antiviral therapy should not consider pregnancy until 6 months after discontinuation of the drug. For male patients on nucleoside (acid) analogue antiviral therapy, there is no evidence of adverse effects of nucleoside (acid) analogue therapy on sperm and the fetus, and fertility can be considered with adequate communication with the patient. The incidence of severe liver disease, cirrhosis, liver function loss and hepatocellular carcinoma can be increased by co-infection of HBV and HCV in 10% to 20% of chronic hepatitis B patients. There are interactions between the two co-infected viruses, mostly in the form of suppression of HBV infection by HCV infection. The treatment of such co-infected patients is based on a combination of the patient's HBV DNA load, HCV RNA load, and ALT status, with different treatment regimens. Co-infected patients who undergo only anti-HCV therapy can be relieved of the inhibitory effect of HCV on HBV infection after effective suppression of HCV, manifesting as activation or exacerbation of HBV infection, and such patients should be monitored for HBV DNA load as well as HBV virological marker levels during treatment. 2, co-infected with HIV: about 6-13% of HIV-infected patients can be co-infected with HBV. HIV co-infection can increase HBV DNA load in HBV-infected patients, reduce the spontaneous HBeAg serological conversion rate, aggravate liver lesions and increase the death rate associated with liver disease in patients. The anti-HBV regimen for patients with HBV/HIV co-infection needs to be established in conjunction with the patient's highly active antiretroviral therapy (HAART) treatment. If the patient needs both anti-HBV and HIV therapy, the anti-HBV drugs can be included in the HAART regimen, such as TDF combined with LAM or TDF combined with emtricitabine (FTC); if the patient's HAART regimen only includes LAM as an anti-HBV drug, attention should be paid to monitoring the patient's HBV resistance and timely adjustment of treatment regimen. If patients do not need HAART for the time being, they can choose ADV, LdT and IFN α for anti-HBV treatment; LAM, TDF and ETV are not recommended for such patients because of the risk of inducing HIV resistance with LAM, TDF and ETV monotherapy. Patients with combined renal disease Antiviral therapy for patients with chronic hepatitis B combined with renal disease includes two main conditions: HBV-related renal damage, mainly the problem of antiviral therapy for HBV-related glomerulonephritis (HBV-AG); (2) combined with other renal disease. It is mainly a problem of antiviral treatment for patients with chronic renal insufficiency. Antiviral therapy is the key to HBV-AG treatment. A number of clinical studies have reported that LAM treatment for HBV-AG can provide significant remission of renal disease with HBV DNA suppression and HBeAg clearance, and clinical trials of ADV have shown that the drug can increase blood creatinine levels in some patients, so ADV should be carefully selected for the treatment of HBV-AG patients. The indications for nucleoside (acid) analogues for the treatment of HBV-AG patients are: patients with confirmed HBV-AG and patients with detectable HBV DNA should be considered for nucleoside (acid) analogues antiviral therapy. There is no consensus on the course of nucleoside (acid) analogs for the treatment of HBV-AG patients. There is no conclusive evidence for the efficacy of generic IFN alpha for HBV-AG, and there is a lack of evidence for Peg-IFN for HBV-AG. For antiviral therapy in patients with combined renal insufficiency, care should be taken to adjust the dosing interval and/or dose according to the patient's creatinine clearance, whether hemodialysis or peritoneal dialysis is available. Specific dose adjustment protocols can be found in the relevant drug instructions. Patients with combined autoimmune thyroid disease Autoimmune thyroid disease is the most common autoimmune abnormality associated with chronic hepatitis B. HBV infection itself is not clearly associated with abnormal thyroid function. The immunomodulatory activity and direct thyrotoxic effect of IFN α as one of the antiviral therapy for chronic hepatitis B may cause worsening of existing autoimmune thyroid disease or the development of new thyroid disease in some patients. In prospective studies of patients with chronic hepatitis B treated with IFN alpha antiviral therapy, 3.6-3.9% of patients showed clinical and/or biochemical thyroid function abnormalities before treatment, and 10.2%-12.3% of patients had positive thyroid autoantibodies (anti-thyroid peroxidase antibody TPOAb, anti-thyroglobulin antibody TgAb) and normal thyroid function. Asymptomatic increases in titers of pre-existing thyroid autoantibodies may occur during antiviral therapy. Less than 10% of patients are autoantibody negative prior to treatment and have newly elevated thyroid autoantibody levels during treatment. Only a small number of patients (2-4.2%) develop abnormal thyroid function from normal thyroid function during treatment. High titers of thyroid autoantibodies (TPOAb titers >18 IU/ml) before treatment correlate with new thyroid abnormalities during treatment. most thyroid abnormalities are reversible after IFN alpha treatment is completed. Therefore, antiviral therapy with IFN α should not be used in patients with uncontrolled thyroid abnormalities. Patients with previous abnormal thyroid function or high pretreatment thyroid autoantibody titers (TPOAb titers > 18 IU/ml) should be monitored during antiviral therapy with IFN α. Patients who develop abnormal thyroid function during therapy should discontinue antiviral therapy if necessary. Patients treated with immunosuppressive or cytotoxic drugs During or after treatment with immunosuppressive or cytotoxic drugs, such as glucocorticoids, anti-CD20, anti-TNF antibodies, etc. in HBsAg-positive patients, elevated HBV DNA load can occur to varying degrees in about 20% to 50% of patients. In some patients, elevated transaminases and jaundice may occur, and in severe cases, fulminant liver failure or even death may occur. Prophylactic treatment with nucleoside (acid) analogues can reduce HBV reactivation. Regardless of the HBV DNA load of HBsAg carriers, nucleoside (acid) analogs are used for prophylaxis 2 to 4 weeks before the application of immunosuppressive or cytotoxic drugs. If the patient’s baseline HBV DNA ≤ 5 log10 copies/ml, consider discontinuing prophylaxis 6 months after the end of immunosuppressive or cytotoxic drug therapy. If the patient has HBV DNA > 5 log10 copies/ml, treatment should be continued until the criteria for discontinuation of antiviral therapy in general patients are met before considering discontinuation. For prophylaxis, HBV DNA inhibiting drugs with rapid effect, such as LAM, LdT and ETV, should be chosen, and for these patients who cannot tolerate recurrent disease caused by viral resistance, it should be combined with the patient’s baseline HBV DNA load, immunosuppressive or cytotoxic drug regimen, and if the duration of prophylaxis is > 12 months, it is recommended to choose drugs with lower incidence of resistance. IFN α is not recommended for prophylaxis in such patients because of its myelosuppressive effect. For HBsAg-negative, anti-HBc-positive patients, there is no unanimous opinion on the use of prophylaxis in these patients while receiving immunosuppressive or cytotoxic drugs, but patients should be closely monitored for HBV virological markers and HBV DNA load. Patients with ALT ≤ 2 times the upper limit of normal value Among patients with ALT ≤ 2 times the upper limit of normal value, two conditions need special attention: (1) patients with high HBV DNA load and ALT (1 to 2) × ULN; (2) patients with normal ALT and age > 40 years. 1, high HBV DNA load and ALT (1-2) × ULN patients: several studies have shown that patients with high HBV DNA load and ALT (1-2) × ULN have poor outcomes regardless of whether they are treated with nucleoside (acid) analogs or IFN alpha. A thorough pretreatment evaluation of such patients is important. Pre-treatment evaluation should include liver pathology and systematic screening for other common causes of mild ALT elevation, such as the presence of HCV co-infection, other non-infectious fatty liver disease (including hepatic steatosis or fatty liver due to alcoholic, autoimmune, or metabolic liver disease), and other conditions that may cause mild ALT elevation. Liver pathology can be used to distinguish between HBV-infected patients in the immune tolerance phase and those with mildly symptomatic chronic hepatitis B. The “immune tolerance phase” is characterized by HBeAg positivity, high levels of HBV replication, normal or low levels of transaminases; liver pathology is mostly free of liver inflammation and necrosis and liver fibrosis. At this stage, the spontaneous negative rate of HBeAg is extremely low, and it is difficult to achieve HBeAg conversion with IFN α treatment, and the application of nucleoside (acid) analogs is prone to drug-resistant mutations; therefore, withholding treatment and regular follow-up are advocated [17](II). Antiviral therapy should be administered to patients with chronic hepatitis B with mild symptoms who have Knodell HAI ≥ 4 or ≥ G2 inflammatory necrosis on liver pathology. IFN α therapy is less effective in such patients and should be chosen carefully; long-term application of nucleoside (acid) analogue therapy is also prone to resistance mutations, so nucleoside (acid) analogs with high resistance barriers (e.g., ETV, TDF) should be selected for monotherapy, or a combination of two drugs without cross-resistance (e.g., LAM or LdT combined with ADV). 2. Patients with normal ALT and age > 40 years [17,28,33]: ALT levels in patients serve as an indirect indicator of liver injury and do not necessarily reflect the true degree of liver tissue inflammation, necrosis and fibrosis. In patients with normal ALT and age > 40 years, especially those with high HBV DNA load (> 5 log10 copies/ml), patients should be actively advised to undergo liver tissue biopsy (II); antiviral therapy is required if there is more than moderate inflammation, necrosis and/or fibrosis (≥ G2/S2); if liver inflammation, necrosis and fibrosis are mild (< G2/S2) then temporary If the liver inflammation, necrosis and fibrosis are mild (< G2/S2), antiviral therapy is not required, but the risk of cirrhosis or liver cancer is increased. Therefore, liver function (including ALT level) should be reviewed every 3-6 months, and AFP and ultrasound should be done. If it is confirmed that the ALT level reaches the indication of treatment or the liver tissue inflammation, necrosis or fibrosis reaches more than moderate level, antiviral treatment is also required, either common IFN α or polyethylene glycolized IFN α (if no contraindication of IFN α is confirmed) or nucleoside (acid) drugs can be used.