Since 2008, we have seen many patients with multi-drug resistance, such as those who had resistance mutations after lamivudine and telbivudine, and then had resistance mutations after switching to adefovir or adding adefovir, and the virus rebounded after applying both drugs, and sequencing found mutation loci for both drugs. Even in some patients, we found that the virus was not controlled with entecavir 1mg (2 tablets) plus adefovir 10mg (1 tablet), and the disease continued to deteriorate. Nucleoside multiresistance is a difficult problem in the treatment of hepatitis B. Multiple drug resistance to nucleoside drugs mainly causes the following evils: 1. hepatitis onset, even severe hepatitis and liver failure. 2. Development of cirrhosis within a short period of time. 3. Some special mutant strains are accompanied by viral surface antigen and C antigen mutations. Some special protein variants can induce hepatocellular carcinoma, which was confirmed by foreign scholars through basic research in 2008, and subsequent clinical studies have confirmed the above findings. We also found that some specific viral variants, when accompanied by abnormal expression of surface antigen/surface antibody/E antigen, have a high incidence of hepatocellular carcinoma in clinical practice. 4. The cccDNA of drug-resistant mutant strains can be preserved in the liver for a long time. The results of basic research suggest that the cccDNA of drug-resistant mutant strains is preserved for more than 5 years. In my case, it was confirmed that the resistant mutation occurred 6 years ago and the nucleoside drug was stopped. 6 years later, the original resistant strain was detected in 2 months with the same drug. Therefore, I guess: it may take more than 10 years to clear the resistant mutant strain. In 2013, foreign experts concluded that the combination of entecavir plus tenofovir for multi-drug resistance might be effective. In April 2013, we treated a renal transplant patient with entecavir plus tenofovir for his combined multi-drug resistance. The combination of entecavir plus tenofovir for 2 months controlled the virus. However, it remains to be seen how long it can be maintained. Nucleoside drug resistance variants have been very common in China. The causes are approximately as follows: 1. using drugs with low resistance genetic barrier as initial medication; 2. intermittent medication and random discontinuation; 3. insufficient dose and reduction of medication; 4. not understanding the resistance spectrum of nucleoside drugs and randomly changing medication; 5. fake drugs are sold in the market. Since 2008, we have replaced nucleoside drugs with interferon to reach the purpose of drug discontinuation. Patients were mainly selected from young people, multi-drug resistant patients without cirrhosis and other contraindications. After stopping the nucleoside drugs, some of the patients developed the disease again, and we treated them with interferon several times to reach undetectable DNA, E antigen conversion, and surface antigen decrease, and the patients reached a sustained response after stopping the drugs. There are specific management protocols for interferon replacement of nucleoside drugs, including selection of the type of interferon used, dose adjustment, monitoring measures, selection of adjuvant drugs, and so on. Improper management is highly likely to result in deterioration of the disease. In 2013, some physicians did not master the treatment protocol and rashly replaced nucleoside drugs with interferon, resulting in the deterioration of the disease in some patients. Therefore, this treatment regimen needs to be applied with caution. Interferon replacement of nucleosides offers a new therapeutic approach to multi-drug resistant treatment, which hopefully will bring benefits to patients.