HBV can mutate naturally during chronic and persistent infection; it can also mutate due to immune stress caused by the human immune response and vaccination. Viral mutation can also be induced by treatment with various antiviral drugs. Recent studies have shown that the half-life of HBV particles is about 4 hours, not 1 day as we used to think, and the shorter the half-life, the faster the virus replicates and the greater the chance of mutation. Second, mutation and drug resistance HBV resistance to antiviral drugs is divided into genotypic resistance (genotypic resistance) and phenotypic resistance (phenotypic resistance). Genotypic resistance refers to the mutation of the viral polymerase gene, forming a new viral gene sequence, which is generally determined by DNA sequencing, gene chips, and other methods. Phenotypic resistance refers to an increase in viral levels during treatment and is generally measured by the concentration of antiviral drugs (IC50). An increase in IC50 indicates a decrease in drug sensitivity or an increase in drug resistance, requiring a higher drug dose to suppress the mutated virus. It has also been reported that phenotypic resistance refers to HBV DNA levels >106 copies/ml accompanied by elevated ALT levels, while genotypic resistance refers to HBV DNA levels of 103 ~106 copies/ml and normal ALT levels. Mutated viruses can often change their biological characteristics and pose a series of problems for the prevention and treatment of chronic hepatitis B. Therefore, in the process of antiviral therapy, it is necessary to strengthen the monitoring of HBV mutation in order to timely adjust the antiviral treatment plan and reduce the liver function damage caused by viral resistance. Third, the current status of viral variants 1. lamivudine. Although it is the first nucleoside analogue approved for the treatment of chronic hepatitis B, it can significantly reduce HBV DNA levels and can normalize liver function and improve liver histology in patients. However, with the prolongation of drug use, HBV resistance has become more and more serious. It is mainly due to the mutation of YMDD in the C region of HBV polymutase. There are several possible outcomes of mutation resistance: ① elevated viral load with normal liver function, usually at the early stage of mutation; ② elevated viral load with abnormal liver function, with most cases showing elevated transaminases at 1~4 months after viral rebound; ③ individual cases with dramatic deterioration and liver function loss. Cases presenting with loss of liver function are mostly concentrated in patients with poor liver foundation or advanced liver disease. Although the introduction of adefovir and entecavir solved the problem of viral rebound and liver function impairment brought about by lamivudine-resistant strains, subsequent clinical trials and treatment revealed that nucleoside analogs such as adefovir and entecavir also had resistant mutant strains. 2. Adefovir. It can effectively inhibit wild strains and lamivudine-resistant strains, and no occurrence of drug-resistant variants was reported at first after one year of treatment, but it was soon found that 50% of patients could not achieve ideal viral suppression, i.e., serum HBV DNA levels decreased <3.5 log10 copies/ml compared with baseline after one year of treatment, or serum HBV DNA >4 log10 copies/ml after 6 months of treatment, for Adefovir resistance variants have been demonstrated, and genotypic resistance increases with longer treatment duration. Genotypic resistance to adefovir increased from zero after one year of treatment to 29% after five years in a group of 125 HBeAg-negative chronic hepatitis B patients who had never been treated with a nucleoside analogue, and recently it has been reported that the rate of resistance to adefovir after 1 to 2 years of treatment was 18-25%, such a high rate of resistance may be due to the change of patients previously resistant to lamivudine to adefovir monotherapy or the use of more sensitive techniques to detect drug-resistant variants. 3. entecavir. Entecavir has more potential than lamivudine for suppressing wild strains of HBV. In patients who have never applied nucleoside analogs, the presence of resistance variants has not been detected after 2 years of application. Although entecavir is used to treat lamivudine-resistant HBV infection, in vitro trials have shown a 6- to 10-fold decrease in activity against lamivudine-resistant strains compared with wild strains, and in a phase III clinical trial of lamivudine-insensitive patients, HBV DNA was detected by PCR in 60% of patients after 96 weeks of treatment, despite the application of high doses (1 mg vs. 0.5 mg). Entecavir resistance variability increased from 4.4% at the start of treatment to 12% at the end of 2 years. Entecavir-resistant variants alone showed only a 6- to 9-fold decrease in susceptibility to entecavir, but a combined variant to lamivudine and entecavir resulted in a more than 1,000-fold decrease in susceptibility to entecavir. Another study reported that after 45 months of discontinuing lamivudine and switching to entecavir monotherapy, all 20 clones isolated from a patient who developed entecavir resistance were confirmed to have lamivudine-resistant variants, such that entecavir is very promising for a patient who has not been treated with a nucleoside analogue, and may not be a good choice for a lamivudine-resistant patient. 4. Lamivudine + adefovir combination therapy: Lamivudine alone rapidly reduces viral titers, and when resistance to the lamivudine genotype occurs plus adefovir to keep the virus below detectable levels. This combination therapy has shown a very good virologic and clinical response over a period of more than 5 years. Similarly, in patients treated with adefovir monotherapy, the addition of lamivudine can further prolong the suppression of HBV. IV. Risk factors for viral mutation Studies have shown that patients with HBV DNA declines of less than 2 log levels (2 log) after 24 weeks of antiviral therapy are considered primary treatment failures, and primary treatment failure is a high risk factor for the development of HBV resistance. High-risk factors for developing resistance to lamivudine have been reported to include prior exposure to lamivudine or famciclovir, high pretreatment ALT levels and high HBV DNA levels (>105 copies/mL) and high pretreatment body mass index. The reason for this is that high pretreatment ALT levels and high HBV DNA imply active viral replication and available space for replication. The association of high body mass index with lamivudine may be due to inadequate drug dosing due to excess weight or hepatic steatosis. Poor response to lamivudine treatment, defined as HBV DNA levels >3 log10 copies/mL at 24 weeks of treatment, is also a precursor to the development of resistance to lamivudine, and organ transplantation, other immunosuppressed individuals including co-infection with HIV also appear to be high risk factors for the development of lamivudine resistance, as HBV is highly replicative in this group. The known risk factors for developing resistance to lamivudine also apply to adefovir, and non-immune tolerant primary patients who present with a poor response or decreased response (<2.5 log reduction in HBV DNA levels at 48 weeks of treatment) are associated with genotypic resistance, and in addition, lamivudine-resistant individuals who are treated with adefovir alone also appear to be susceptible to developing resistance to adefovir, as reported in a Korean study in which lamivudine-resistant patients were treated with adefovir for one year. In a report from Korea, 19% of patients treated with adefovir for one year had developed resistance to adefovir. When lamivudine resistance occurred, the addition of adefovir reduced the incidence of resistance. In a group of Italian patients treated with the two drugs in combination for 2 years, none developed resistance to adefovir. The study found that those who started adefovir treatment as soon as genotypic resistance developed achieved viral suppression and normalized ALT levels more quickly than those who delayed treatment. Therefore, it is recommended that adefovir be added as soon as lamivudine resistance is detected, rather than substituted. Although resistance to both lamivudine and adefovir has rarely been reported, if it occurs, susceptibility to entecavir, tenofovir and interferon is still maintained. V. Countermeasures against mutations 1. Before treatment: liver puncture, abdominal ultrasonography, detection of serum AFP, liver biochemistry, blood routine, HBV serology (HBeAg, anti-HBe) and HBV DNA quantitative testing. 2. Under treatment: liver biochemistry every 1-2 months, quantitative HBV DNA testing every 3-4 months, HBeAg, anti-HBe testing every 6 months, routine blood tests every 6 months, abdominal ultrasound every 6-12 months, serum AFP testing (high risk groups should be monitored frequently), and outpatient visits at least every 6 months to ensure good compliance. 3. When drug-resistant strains are suspected to occur: first, we should rule out poor efficacy or ineffectiveness due to poor compliance, then perform liver biochemistry, quantitative HBV DNA testing, HBeAg, anti-HBe, and if possible, determine genotypic resistance (e.g. sequencing, linear probe assay), and consider antiviral remedial drugs. 4, from experience in the treatment of HIV infection, to prevent the occurrence of antiviral drug resistance, the rational application of antiviral drugs can avoid and reduce the emergence of drug-resistant HBV strains, therefore, before starting antiviral therapy, first, carefully consider factors such as host, environment and virus, they may have a high impact on the natural history of chronic HBV infection, for those with normal transaminase levels and mild lesions on liver biopsy should not antiviral therapy, except for those undergoing chemotherapy or immunosuppressive therapy. Second, individualized treatment regimens for antiviral drugs should be based on the effectiveness of the drug, safety, severity of disease, and prior treatment history. Particular attention should be paid to the incidence of drug resistance, risk factors, and manifestations of drug-resistant HBV. In addition, pay attention to potential cross-resistance between existing oral antivirals when starting antiviral remedial therapy or combination therapy. Again, foresighted surveillance for drug-resistant HBV is an important part of controlling disease to reduce the incidence and sequelae of drug-resistant HBV. Sensitive assays can detect drug-resistant HBV subspecies before viral or biochemical breakthrough occurs, and appropriate remedial therapy should be used. Finally, the use of single-agent, sequential antiviral therapy for chronic hepatitis B may lead to an increase in multidrug-resistant HBV; therefore, trials on the safety and efficacy of combination antiviral therapy for chronic HBV infection are also called for. VI. Conclusion Because of the high chance of spontaneous mutation of HBV, coupled with the persistence of libraries in the liver that provide HBV replication such as cccDNA, it is not surprising that resistance to long-term application of HBV polycombase inhibitors occurs. The high incidence of resistance to lamivudine is also the most commonly encountered problem in clinical practice, followed by adefovir and again entecavir. Most experts predict that extended monotherapy will inevitably select out resistant strains in primary care patients, even with the application of more potent drugs such as entecavir and tenofovir (tenofovir). Although the incidence of drug resistance varies widely, the clinical presentation is similar and consists of three types, namely asymptomatic viremia, elevated serum ALT levels, and occasional loss of compensability. Combination or dual nucleotide/nucleoside analogs for different target drugs may be superior to monotherapy.