The most fundamental treatment for chronic hepatitis B is antiviral, and there are two major classes of anti-hepatitis B virus drugs, one is alpha-interferon and the other is nucleoside (acid) analogs. It has been 18 years since the first nucleoside (acid) analogue lamivudine was introduced in 1991, and during these 18 years, adefovir (ester), entecavir and telbivudine have been marketed in China. These nucleoside (acid) analogues have a definite anti-hepatitis B virus effect and are convenient to take orally with few side effects, and are favored by many patients and clinicians. However, with the prolongation of treatment time, the resistance of hepatitis B virus to nucleoside (acid) analogues has gradually emerged and has become a prominent problem in the field of liver disease treatment. The resistance of hepatitis B virus to nucleoside analogues is related to the characteristics of drug action and the biological characteristics of the virus. Nucleoside (acid) analogs do not kill the virus, but merely impersonate the nucleoside (acid) raw materials required for virus replication and inhibit the reproduction of the virus, and once the virus discovers this error, it will correct itself through mutation of the gene locus. Therefore, the phenomenon of drug resistance is an adaptive change of the virus for its own survival under external pressure, which is a common phenomenon in the biological world and is in line with Darwin’s “survival of the fittest” theory of biological evolution. In the process of taking nucleoside (acid) analogues for a long time, virus resistance is absolute and non-resistance is relative. So, how can we tell if a virus is resistant to a drug? In fact, the method is very simple. If a patient’s viral level suddenly rises from a low level (or undetectable level) to a high level during the course of taking a nucleoside (acid) analogue, sometimes even accompanied by an increase in serum transaminases, it can be considered that the virus is resistant to the drug, and the diagnosis can be clarified by performing the corresponding resistance site test. Different nucleoside (acid) analogues have different resistance rates and resistance characteristics: lamivudine and telbivudine have relatively high resistance rates and there is cross-resistance between them; entecavir has a low resistance rate, but if lamivudine or telbivudine resistance occurs, the resistance rate of entecavir will also increase significantly; adefovir also has a low resistance rate and is not affected by other nucleoside (acid) analogues. Viral resistance is detrimental to treatment, when viral replication will be active again and may aggravate liver damage, so viral resistance must be taken seriously. So, what if the virus is resistant to the drug? 1. If it is lamivudine resistance: First, add or switch to adefovir; second, switch to entecavir and double the dose (2 tablets/day); because there is cross-resistance with telbivudine, you cannot switch to telbivudine. 2. If it is telbivudine resistance: the treatment is the same as lamivudine resistance, that is, add or switch to adefovir; or switch to entecavir. 3, if it is adefovir resistance: one is to add or switch to lamivudine or telbivudine; the second is to directly switch to entecavir. 4.If it is entecavir resistance: you can add or switch to adefovir; because entecavir resistance is based on lamivudine and telbivudine resistance, so you cannot switch to the latter two drugs. 5. Regardless of which nucleoside (acid) analogue is resistant, you can switch to alpha-interferon under the guidance of a specialist, provided that there are no contraindications to the use of alpha-interferon. No matter which nucleoside (acid) analogue is resistant, as long as the liver function remains normal, the drug can also be discontinued under the guidance of a specialist, but the process of discontinuation must be closely observed, if the liver function is obviously abnormal and not easily controlled, the oral nucleoside (acid) analogue antiviral therapy should be reintroduced. 7. Patients with decompensated cirrhosis (with ascites, jaundice, etc.) must adhere to lifelong nucleoside (acid) analogue antiviral therapy, even if drug resistance occurs, do not hastily stop the drug, otherwise the condition will deteriorate rapidly.