China is a large hepatitis B country, with about 10-12% of the population infected with hepatitis B. Longitudinal studies have found a 5-year cumulative incidence of cirrhosis of 8%-20% in patients with untreated chronic hepatitis B. About 20% of patients with untreated compensated cirrhosis develop decompensated cirrhosis cumulatively over 5 years [2C4,11C13], and 14-35% of patients with untreated decompensated cirrhosis survive for 5 years [2C4,12]. Primary liver cancer occurs in approximately 2-5% of patients with hepatitis B cirrhosis each year [13]). The natural history of hepatitis B virus infection is divided into 5 phases: 1. Immunotolerance phase. It is also known as our common major triple-positive with normal liver function. This stage is mostly seen before adolescence and also belongs to the healthy carrier stage. 2. HBeAg-positive immune activation stage. Clinically common major triplet positive with repeated abnormal ALT. 3, Inactive HBV carriage stage. Mostly seen in small triplets with normal liver function and low level of viral replication. 4. HBeAg-negative slow hepatitis B stage. Small triplet positive, or 1 or 5 positive, but liver function is again repeatedly abnormal. 5.HBsAg-negative stage. Mostly seen in 2, 4, 5 positive stage with stable liver function. negative HBVDNA. Note: Cirrhosis can occur in all of the above stages except the immune tolerance stage, or liver cancer can occur, only the incidence of each stage is different. The response to hepatitis B antiviral clinical treatment is answered according to the following 10 questions: 1. How should liver disease be assessed before treatment? 2.Treatment goals and endpoints? 3.Definition of response? 4. Selection of first-line therapeutic agents? 5. Prediction of treatment response? 6. Definition of drug resistance and how to deal with drug resistance? 7.How to monitor treatment? 8.When should treatment be interrupted? 9.How to treat special populations? 10. What are the topics outside of antiviral therapy? 1.How should liver disease be evaluated before treatment? First, the relationship between liver disease and HBV should be assessed, as well as the severity of liver disease, all immediate family members and sexual partners should be tested for HBV-M, and HBV-M negative should be vaccinated. Because of the presence of an immune tolerance period with normal ALT and an inactivation period with intermittent normal ALT, prolonged follow-up should be performed. Every 3 months. Liver disease evaluation items are as follows: 1) ALT,AST,AKP,GGT,TBIL,ALB,globulin,PT,blood work,ultrasound. 2) HBVDNA.(WHO recommends using IU/ml to indicate the level of HBVDNA. It is recommended to replace copies/ml with IU/ml. 1IU Ì 5.6 copies/ml, 10E4 copies/mL Ì 2000 IU/mL) 3) Whether there is co-infection. Such as HIV, HDV. and whether there is alcoholic liver or AIH, metabolic liver disease. Anti-HAV negative patients are recommended to use HAV vaccine. 4) Liver tissue biopsy can assist in deciding whether to treat. Transient elastography provides a good non-invasive examination of cirrhosis, but the results are unreliable with elevated ALT. 2.Treatment goals and endpoints? Goal: To improve the quality of life of patients with chronic hepatitis B (CHB) and to stop the progression to cirrhosis, decompensated cirrhosis, and primary liver cancer. Endpoint: The ideal endpoint is the disappearance of HBSAg, and the realistic endpoint is sustained virological negativity. 1) E antigen positive or negative patients who experience disappearance of surface antigen will achieve long-term remission even without the presence of surface antibodies. 2) Sustained virologic negative regression with a biochemical response, disappearance of E antigen, and persistent appearance of antibodies will also result in long-term remission in most patients. 3) Persistent undetectable virus may also be a better treatment endpoint after long-term antiviral therapy. Note: Although relatively short in duration, interferon has high side effects, high short-term costs, and a low proportion of patients achieving the desired endpoint. In contrast, although nucleoside analogs are convenient for treatment, they require long-term treatment, and viral mutations may occur during treatment, making the ideal endpoint difficult to achieve. This is related to the long-term stable presence of hepatitis B virus cccDNA in hepatocytes, which is difficult to be cleared. Studies have found that cccDNA and HBSAg are positively correlated, and the disappearance of HBSAg can indicate the cure of hepatitis B to some extent. In addition, virological studies have found that the half-life of cccDNA is about 8 months, and virologists believe that if the replication of the virus can be completely inhibited so that the cccDNA pool cannot be replenished, it will take about 16 years for the decay to complete. Therefore, antiviral therapy is a long-term process that requires the full understanding and cooperation of the patient. 3. What is the definition of response? Response is divided into biochemical, serological, virological and histological responses. The response is also divided into two parts for drugs, one is interferon (IFN) and the other is nucleoside analogs (NAs). Interferon: Whether biochemical response persists should be followed for at least 1 year after discontinuation of the drug, every 3 months, and some patients should be followed for 2 years to further determine whether a sustained response has occurred. Serologic response is the conversion of E antigen positivity to antibody positivity and surface antigen to surface antibody. Virologic response is HBVDNA < 2000 IU/ml. at 6 months after treatment and maintained for 6 to 12 months after discontinuation of the drug. Sustained virologic response is HBVDNA < 2000 IU/ml. for at least 12 months after discontinuation of therapy. NAs treatment: 1. Primary non-response means HBVDNA decreases < 1 log10 IU/ml relative to baseline 3 months after treatment. 2. Virologic response means HBVDNA is below detection line and is tested every 3-6 months. 3. Partial response: HBVDNA decreases > 1 log10 IU/ml 6 months after treatment. 4. Virologic breakthrough: HBVDNA levels increase 1 log10 IU/ml from treatment 5, HBV resistance to NAs (drug resistance) 6, NAs discontinuation There is no general practice data. A small number of patients can be discontinued, the definition of discontinuation is the same as interferon Tissue response: 1, complete response: virological response plus the disappearance of HBSAG, 2, partial response: HAI score decreased by more than 2 points. 4, the choice of first-line treatment drugs? Indications for treatment: HBVDNA> 2000 IU/ml, abnormal ALT, or severe liver disease. Immunotolerant patients: E antigen positive: age < 30, normal ALT, high viral load, no family history of HCC and cirrhosis, no evidence of liver disease may not be treated or biopsied, but should be followed up once every 3-6 months, over 30 years old, family history of HCC and cirrhosis should be considered for biopsy or treatment. E antigen negative: normal ALT, viral load between 2000 -20,000 IU/ml, no evidence of liver disease, no treatment or biopsy. However, they must be followed closely for 3 years, and after 3 years they should be followed for life as non-activated CHB patients, and the degree of cirrhosis should be evaluated noninvasively. Antiviral therapy in immunologically active chronic hepatitis B patients, whether E antigen positive or negative, are faced with two options, 1. interferons. 2. NAs. The advantages of interferons are limited duration of therapy (generally 12 months), no risk of resistance, higher seroconversion rate (HBsAg disappearance rate at 12 months after 6 months of PEG-IFN-2a treatment at 3%, increasing to 9% at 3 years, and 12% at 5 years). The rate of HBsAg disappearance with NA treatment is 0.). Disadvantages are moderate antiviral efficacy, risk of serious side effects, poor tolerability, and the need for subcutaneous injections. The advantages of NAs are efficient viral suppression, good tolerability, and ease of oral administration. Disadvantages are: undefinable regimen requiring long-term treatment, risk of viral mutation, and unknown long-term safety of some drugs. The rate of NAs resistance is shown in the following chart: Most patients in China who are infected with hepatitis B virus through mother-to-child transmission experience a state of immune tolerance. At this time, because the child's immune function is not yet complete, the immune system is not yet able to recognize the hepatitis B virus, and antiviral therapy is not effective at this time. As they grow older, the immune function of middle and high school students gradually improves, and the immune system of the infected person gradually begins to recognize the hepatitis B virus, and the immune cells attack the virus repeatedly. This is the best time to choose immunomodulatory and antiviral "two-pronged" interferon therapy or other antiviral treatment methods, which can effectively inhibit hepatitis B virus replication, in order to obtain long-term stability and effective control of disease progression, is the best time for antiviral treatment. As antiviral drugs have their own characteristics, specific treatment plans need to be communicated specifically with clinicians. Note: PEG-IFN-2b , emtricitabine and tenofovir are not currently allowed to be used for hepatitis B treatment in China. . 5.Prediction of treatment response? 1) Interferon Before treatment: E antigen positive CHB, HBVDNA <2 * 10E8 IU/ml, ALT 2-5 times, HBV genotype A or B has higher rate of surface antigen disappearance than D/C. During treatment: E antigen positive CHB with HBV DNA <20,000 IU/ml at 12 weeks with a 50% chance of anti-HBe serological conversion [105]. Recent data suggest that HBsAg <1500 IU/ml at 12 weeks is a strong predictor of anti-HBe serologic conversion [107,108]. If HBsAg >20,000 IU/ml at 12 weeks or no change in HBsAg quantification suggests a very low likelihood of anti-HBe seroconversion [107C109]. E antigen-negative CHB with HBV DNA <20,000 IU/ml at 12 weeks has a 50% chance of sustained response after drug discontinuation. Several recent studies have shown that HBsAg decline predicts virologic response and HBsAg disappearance [113C115]. 2) NAs: pre-treatment: E antigen positive CHB, HBVDNA <2 * 10E8 IU/ml, ALT 2-5 times, high anti-HBe seroconversion. Viral genotype has no effect. During treatment: virological response at 24 weeks of lamivudine, telbivudine treatment ( HBVDNA below detection line) predicts low resistance rate. How to choose interferon and NA therapy: The mainstream view is that interferon is non-resistant, has a relatively short course and has high serological conversion. NAs monotherapy is preferred to entecavir or tenofovir (high resistance barrier) and the other 3 NAs are only chosen when the first 2 drugs are not available or are determined to be effective or for certain specific reasons (e.g., other severe disease, cirrhosis). 6.Definition of drug resistance and how to deal with drug resistance? Drug resistance is defined as a decrease in the patient's viral load <2log after treatment with NAs, or the reappearance of a negative viral load in the blood after it has turned negative. Failure of NAs therapy is preferred to distinguish between primary nonresponse (possible in about 10-20% of patients with ADV) and virologic breakthrough. Drug selection is based on genetic resistance loci. _ Lamivudine resistance: switch to tenofovir (or add adefovir if tenofovir is not available) (B1). _ Adefovir resistance: If patient is not pre-susceptible to adefovir, switch to entecavir or tenofovir (B1); entecavir is preferred for patients with high viral load (C2). If the patient is congenitally lamivudine-resistant, switch to tenofovir (C1). _ Telbivudine-resistant: switch to tenofovir (or add adefovir if tenofovir is not available) (C1). _ Entecavir resistance: switch or add tenofovir (or add adefovir if tenofovir is not available) (C1). Tenofovir resistance: There are no data on tenofovir resistance and therefore no experience. However, the resistance sites should be supplemented with entecavir, telbivudine, lamivudine, or emtricitabine (C2). Entecavir may be better, especially in patients who have used lamivudine before (C2). 7. How is treatment monitoring done? Interferon: Blood tests, ALT every month. TSH every 3 months. All patients are monitored for safety during the 12 months of treatment. HBeAg, anti-HBe and HBV DNA should be tested at 6 months, 12 months and 6-12 months after treatment. If HBV DNA is negative and anti-HBe is positive within 12 months, HBsAg should be quantified and monitored. If HBsAg negative turn should be monitored anti-HBs. level. E antigen positive patients with HBsAg > 20,000 IU/ml for 3 months of treatment or no change in HBsAg and low likelihood of E antigen conversion [107C109]; it is recommended to consider discontinuing PEG-IFN therapy. E antigen negative patients should be monitored for HBsAg quantification if HBVDNA remains negative for 12 months. The rest are the same as for E antigen-positive patients E antigen-negative patients are recommended to consider discontinuing PEG-IFN therapy if HBsAg does not decrease and HBV DNA decreases below 2 log10 IU/ml for 3 months of treatment [111,112]. NAs: monitor ALT, HBV DNA every 3 months and quantitative two-and-a-half half yearly. Telbivudine : additional monitoring of creatine kinase is required to observe for muscle soreness. Adefovir: additional monitoring of renal function, serum phosphorus, urine routine Entecavir: monitoring of serum lactate concentration or carbon dioxide binding rate is required when there is muscle discomfort or nausea. 8. When should treatment be interrupted? See 7 for interferon therapy. NAs therapy may be long term and discontinuation of therapy may be required until HBsAg disappears, especially in patients with cirrhosis. HBsAg should be monitored once every 12 months. 9.How to treat special populations? The dose of NAs should be adjusted according to creatinine clearance in patients with renal disease. Also monitor creatinine level. Blood concentration monitoring, effect of tenofovir on bone density in patients with cirrhosis, myopathy caused by tenifovir, long-term carcinogenic effect of entecavir and tenofovir are yet to be studied. The use of interferon is contraindicated in patients with cirrhosis B. Entecavir and tenofovir are preferred for consideration. However, the likelihood of lactic acidosis is higher with entecavir in patients with decompensated cirrhosis (MELD score >20) [153]. Even with effective NAs, the incidence of HCC remains high in such patients and does not even stop the progression, so regular monitoring of ultrasound, AFP and, if necessary, liver transplantation is still required. Treatment with NAs with a high resistance barrier is recommended before liver transplantation. lamivudine or adefovir in combination with HBIg reduces graft reinfection with < 10% infection rate [155,157,158]. Entecavir is also effective and safe in blocking HBV re-infection without HBIG prophylaxis [159]. HIV co-infected patients: tenofovir, emtricitabine, and lamivudine are recommended for control. Patients with HDV co-infection: (PEG-)IFN is the only drug effective against HDV [178C183], detection of HDV RNA 3-6 months after treatment, and 1 year of treatment may be necessary and may benefit from a longer course. However, there are no published data to determine the duration of therapy. Although NAs are not effective against HDV, control of HBVDNA at 2000 IU/ml may be required. HCV co-infection: Treatment of HCV with NAs to control HBV replication. Acute hepatitis: use of NAs may be beneficial, but not supported by data from large samples. (A1). Children: should be critically evaluated prior to treatment. Only conventional interferon, lamivudine, and adefovir have safety and efficacy data available. Pregnancy: IFN is contraindicated. the FDA classifies lamivudine, adefovir, and entecavir as Class C, and tipifovir and tenofovir as Class B. Lamivudine and telbivudine have been shown to be safe in treating HBsAg-positive pregnant women with high viral load (HBV DNA >10E6C7 IU/ml) after 3 months of gestation and to reduce the odds of intrauterine transmission and perinatal transmission (with both active and passive immunization given by the BB) [208,209,211C213] (B1). If a pregnant woman is not on antiviral therapy, especially after delivery, she is at risk of developing hepatitis activity. Close follow-up is warranted. The safety of breastfeeding while on antiviral therapy is unknown and breastfeeding may be forgone. Tenofovir concentrations in breast milk have been reported with limited oral bioavailability during the period, so the infant is only exposed to small concentrations and is considered safe. Immunosuppressed patients: Patients with HBsAg and anti-HBc positivity prior to immunosuppressive therapy or chemotherapy should be tested for HBV DNA levels and monitored, and should be treated with prophylactic NAs antiviral therapy. Patients with renal failure and renal transplantation: These patients should be vaccinated if they do not have hepatitis B. CHB combined with renal insufficiency can be treated with interferon or NAs with dose adjustment. The treatment dose should be further adjusted during treatment according to the results of renal function monitoring. Also comorbidities such as hypertension and diabetes mellitus should be controlled. Interferon should be avoided in renal transplant patients and NAs are recommended for prophylaxis. Patients with extrahepatic manifestations of damage: e.g. skin damage, nodular arteritis, etc., the use of interferon may worsen the disease. There are very few controlled studies in this area, case reports show that NAs treatment is effective, lamivudine has more data to support it, entecavir, tenofovir may be more effective. 10. Topics other than antiviral therapy? Now many hospitals and hepatologists are talking about antiviral. As if there is no other treatment except antiviral. In fact, antiviral is only a means, the purpose is to quell liver inflammation. If the hepatitis is still not quiescent after antiviral, on the one hand, we have to look for the cause, and on the other hand, we have to reduce or suppress the liver inflammation. In particular, the control of liver inflammation should be given priority. Failure to control liver inflammation suggests that liver function is declining, and once liver function fails, the person’s life will cease to exist even without the virus. Therefore, when NAs are antiviral, they should be combined with liver-protective drugs or Chinese herbal medicine for a period of time to normalize ALT early. Those treatments that proved to be effective when there were no NAs should be used in combination (e.g. licorice analogs, wu wei zi analogs). Antiviral therapy, especially with interferon antiviral therapy, can be appropriately supplemented with immunomodulatory therapy may be beneficial. Patients with hepatitis B are not immunocompromised, but rather immune imbalanced. Current research has confirmed this. The development of hepatitis B is mainly caused by a relative decrease in the function of helper suppressor T lymphocytes, resulting in an increase in the function of relative helper killer T lymphocytes. The current immunomodulatory drugs on the Western side are all immune enhancing (e.g. thymidine). Sometimes it may not have the expected effect. Therefore, in the regulation of immunity can be appropriate to consider Chinese medicine treatment, because, Chinese medicine is concerned with balance, from the universe to the small to the human internal environment, all need to be in a state of balance. Western medicine talks about the stability of the human internal environment, which is a balance, once the internal environment is not stable, then people will not survive. Therefore, whether it is the balance of immunity, or the balance of the internal environment, and the balance of human and natural environment, eventually, Western medicine and Chinese medicine will go the same way. Patients with hepatitis B cirrhosis should be given life coaching, especially those who are decompensated. For example, avoid unclean diet, especially raw food including fruits, salty food and other foods, because the risk of developing infection is greater than the benefit of eating fruits. It is also clinically possible to see patients who have normal liver function every time still have cirrhosis, which is thought in the literature to be caused by mild inflammation. Some of this group have HBVDNA below the detection line, should they be antiviral? Should they be treated with antifibrotic therapy? There is no answer and no systematic study. Patients are advised to have their liver biopsied.