Antiviral therapy for chronic hepatitis B is a long-term process, and long-term antiviral therapy may pose a risk of drug resistance, leading to disease progression and increasing the incidence of cirrhosis, liver failure and liver cancer. Data show that more than 80% of hepatitis B patients currently receiving antiviral therapy in China are still treated with low potency and high resistance drugs, while other countries and regions are already using strong and low resistance drugs. To strengthen the management of hepatitis B virus drug resistance, the emphasis is on prevention: 1. Understand the past treatment history of patients with hepatitis B. First, patients should be asked in detail about the type, dose, efficacy and resistance of previously applied nucleoside (acid) drugs, which is an important guide for the development of follow-up programs. 2. Initial drug selection. Initial selection of potent, high resistance genetic barrier nucleoside (acid) analogues is the most effective strategy to prevent drug resistance. The consensus or guidelines of the Asia-Pacific, European and American hepatology societies for the treatment of chronic hepatitis B recommend that patients with initial treatment with nucleoside (acid) drugs should choose strong, highly resistant genetic barrier antiviral drugs, namely ETV and tenofovir (TDF, not yet available in China) as the preferred or first-line monotherapy. Our guidelines also recommend that “if conditions permit, initial treatment with a drug with a strong antiviral effect and a low incidence of drug resistance is preferable”. The initial selection of highly resistant genetic barrier drugs not only reduces the occurrence of drug resistance and the complications associated with drug resistance, but also eliminates the need for genotypic drug resistance testing before treatment, reduces the number of treatment monitoring, and reduces the need for salvage therapy and saves related costs. 3. Patient education. Studies have shown that up to 40% of virological breakthroughs may not be related to drug resistance, but rather to poor patient adherence. The survey showed that 22%-27% of patients in China lack awareness of the seriousness of drug resistance and the importance of long-term treatment with nucleoside (acid) analogues, only 46.3% of chronic hepatitis B patients recognize the importance of antiviral therapy, and most patients have high expectations of antiviral therapy, which is an important reason for poor compliance, and nearly half of patients discontinue their own medications, which is also an important reason for the occurrence of drug resistance in LAM treatment. Strengthening patients’ awareness of the disease and compliance education can help improve patients’ understanding of the importance of long-term treatment and reduce the occurrence of drug resistance. 4. Avoid random sequencing of single drugs. The risk of multi-drug resistance mutation and cross-resistance can be induced by single-drug sequencing. Another study showed that switching to ETV after LAM treatment resulted in a poorer virological response and was prone to drug resistance. 5. Strictly control the indications for treatment. In order to reduce the risk of drug resistance, the indications for treatment should be strictly mastered to avoid unnecessary treatment. For example, patients with mild liver inflammatory lesions and difficulty in obtaining a sustained response (e.g. patients with normal alanine aminotransferase levels, high viral load, hepatitis B e antigen-positive immune tolerance) should avoid treatment with nucleoside (acid) analogues.