With new anti-hepatitis B virus drugs coming onto the market, the experience of hepatitis B antiviral treatment has been enriched. The traditional enzyme-lowering p-hepatoprotective and Chinese herbal medicine treatments are gradually becoming obsolete, because although these drugs can reduce serum aminotransferase levels for a while, they can’t really extinguish the inflammation inside the liver tissue. China’s “Chronic Hepatitis B Prevention and Control Guidelines” especially emphasizes the importance of hepatitis B antiviral treatment. At present, there are two major classes of drugs available for hepatitis B antiviral treatment: interferon and nucleoside (acid) analogs. Interferon analogs have a relatively fixed course of treatment and a high HBeAg serologic conversion rate. However, the side effects are large, the efficiency is low, and there are many contraindications. Nucleoside (acid) analogs are orally administered, easy to use, adverse reactions are not obvious, the disadvantage is that long-term medication is required, and drug resistance is likely to occur. Once drug resistance occurs, the ability of the original effective antiviral drugs to inhibit viral replication will be greatly reduced, and at this time, even if the dose of the drug is increased or changed, the efficacy may not be as good as the initial treatment. At the same time, drug resistance can lead to recurrence and deterioration of the disease, and cross-resistance between drugs also makes the choice of subsequent treatment extremely difficult. However, drug resistance is also preventable and treatable. Therefore, it is useful for hepatitis B patients to know about drug resistance so that they can neither ignore nor panic about the problem of drug resistance. First of all, understand the two concepts of hepatitis B virus resistance to nucleoside (acid) analogs: (a) genotypic resistance. This refers to a specific mutation in the hepatitis B virus gene. These mutation points have been experimentally confirmed to be closely related to drug resistance. Serum HBV DNA levels remain undetectable when genotypic resistance occurs. (ii) Phenotypic resistance Phenotypic resistance has two different meanings: first, a pharmacologic or virologic definition. It refers to a marked decrease in the susceptibility of a viral strain to a drug in an in vitro drug sensitivity assay system. Second, clinical resistance. The presence of a specific key resistance mutation along with a rise in viral load and elevated transaminases. How to prevent drug resistance? It is a basic principle of medicine that prevention is better than cure. The rational application of nucleoside (acid) analogs for the treatment of hepatitis B is the most effective measure to prevent the occurrence of drug resistance. During the medication period, we should emphasize drug compliance and take the medication regularly and on time as prescribed by the doctor. For HBeAg-positive patients with mild disease or in the immune tolerance period, nucleoside (acid) analogs should not be selected for treatment, especially for young (<30 years old) patients. For antiviral therapy, if possible, choose the drug with the highest antiviral activity and the lowest incidence of genotypic resistance, which is also known as a drug with a high genetic barrier to resistance, such as entecavir. Regularly test for hepatitis B virus mutation and change antiviral drugs as soon as genotypic resistance is detected to avoid the emergence of clinical resistance. How to deal with the emergence of drug resistance? After the occurrence of drug-resistant mutation of hepatitis B virus, the disease rebounds, increasing the difficulty of subsequent treatment. However, the majority of patients should not panic, in recent years, new anti-hepatitis B virus drugs are constantly being developed and applied in the clinic, and there are some effective measures for the previous very difficult drug resistance problem, which can be called salvage treatment. Such as lamivudine resistance, can be combined with adefovir or change to entecavir; adefovir resistance can be changed to tenofovir; entecavir resistance can be changed to adefovir or tenofovir. Nucleoside (acid) analog resistance can also be switched to polyethylene glycol interferon or regular interferon antiviral therapy.