Drug resistance is an important barrier to the efficacy of anti-hepatitis B virus therapy with nucleoside (acid) analogues. When nucleoside (acid) analogs are used for long-term treatment, drug resistance is more common. Drug resistance can not only cause loss of therapeutic effects achieved (e.g., histological improvement, etc.), but can also lead to dramatic deterioration of liver lesions and disease progression (e.g., hepatitis rekindling, liver decompensation, liver failure, etc.). Several studies have shown that the incidence of cirrhosis and hepatocellular carcinoma is significantly higher in drug-resistant patients than in non-drug-resistant patients. Cross-resistance and multi-drug resistance will increase the difficulty of subsequent treatment and limit the options for re-treatment. The spread of drug-resistant virus strains may lead to serious public health problems, and drug-resistant-induced rtA181T/sW172* mutant strains may be potentially carcinogenic, with a 30% and 1.8% incidence of hepatocellular carcinoma at 26 months in patients with and without mutant strains, respectively, at follow-up. In addition, drug resistance significantly increases the medical cost of long-term treatment. Based on the serious harm of drug resistance, prevention of drug resistance is crucial. The serious problem of drug resistance of nucleoside (acid) drugs in China is related to the unregulated use of these drugs and the lack of awareness of drug resistance among doctors and patients. A survey shows that the awareness of the importance of drug resistance among doctors in China is significantly lower than that in Korea and the United States; among patients treated initially with nucleoside (acid) drugs in countries and regions such as Europe, the United States, Japan and Korea, the proportion of patients using high-efficiency, low-drug-resistant nucleoside (acid) drugs is 80% to 90%, while up to 81% of patients in mainland China still use low-efficiency, highly drug-resistant nucleoside (acid) drugs for initial treatment, of which 30% use Lamivudine (LAM) and 35% of patients with domestic adefovir (ADV). At the same time, there are many irregularities during the treatment of patients with nucleoside (acid) drugs, such as single drug random sequences, frequent drug changes or drug additions, and unreasonable drug additions or drug changes after drug resistance, etc. About half of the patients stopped the drugs by themselves. Mechanisms of drug resistance and detection Mechanisms of drug resistance The generation of drug-resistant strains of HBV can be explained by an evolutionary perspective. Due to the characteristics of high replication rate and low fidelity of hepatitis B virus, it is prone to mutation, and after the screening of drug pressure (including the target of action, pharmacokinetic barrier, resistance genetic barrier, antiviral drug efficacy and resistance pathway), and then through the process of environmental adaptation (intrahepatic replication space and adaptation), drug-resistant virus strains eventually emerge. Among the four nucleoside (acid) analogues currently approved for marketing in China, LAM has the highest incidence of resistance and entecavir (ETV) the lowest. Drug resistance detection means clinical drug resistance monitoring mainly includes HBV replication level monitoring and follow-up and liver biochemical index testing, and sensitive or relatively fixed detection techniques should be used. At present, China lacks standardized, standardized and unified genotypic drug detection methods, commonly used technologies include nucleic acid sequence analysis, restriction fragment length polymorphism analysis, linear probe reverse hybridization technology, gene chip technology, etc., which have their own advantages and disadvantages and must yet be standardized. Key points of drug resistance management Primary non-responder management should confirm patient compliance, followed by sequencing of the HBVRT gene region to identify possible drug resistance mutations, so that early replacement with more effective drugs or addition of potent, non-cross-resistant drugs can be targeted. Partial response management adjusts the regimen based on the antiviral efficacy of the drug and the resistance genetic barrier after patient compliance is confirmed. It is important to note that the management of partial virologic responses at 48 weeks of treatment with potent, low resistance agents (e.g., ETV) is still controversial. This can be considered based on the patient’s HBV DNA levels at baseline and at 48 weeks of treatment and the dynamics of HBV DNA during treatment. If the original drug can be continued for those with high viral load at baseline and sustained HBV DNA decline, virologic response can still be obtained with prolonged treatment and resistance rate is very low. HBVDNA should be monitored regularly during salvage therapy with nucleoside (acid) analogues for early detection of virological breakthrough. Once virologic breakthrough occurs, salvage therapy should be promptly added with a non-cross-resistant antiviral drug if the patient’s compliance is confirmed. The addition of pegylated interferon (PEGIFN) may also be considered, but for safety reasons, tibivudine (LdT) should not be used in combination with PEG IFN. The first step is to ask the patient about the type, dose, efficacy and resistance of the nucleoside (acid) analogues used in the past, which is an important guide for the development of the follow-up plan. Initial drug selection Initial selection of potent nucleoside (acid) analogues with high resistance genetic barriers is the most effective strategy to prevent drug resistance. The Asia-Pacific, European and American hepatology societies’ consensus or guidelines for the treatment of chronic hepatitis B recommend that patients with initial treatment with nucleoside (acid) drugs should choose potent, high-barrier antivirals, 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, drugs with strong antiviral effects and a low incidence of drug resistance should be selected for initial treatment”. The initial selection of a highly resistant genetic barrier drug not only reduces the incidence of resistance and the complications associated with resistance, but also eliminates the need for pre-treatment genotypic resistance testing, reduces the number of treatment monitoring visits, and reduces the need for salvage therapy and the associated costs. Patient education studies have shown that up to 40% of virologic breakthroughs may not be related to drug resistance, but rather to poor patient adherence. Surveys show that 22-27% of patients in China lack awareness of the severity of drug resistance and the importance of long-term treatment with nucleoside (acid) analogues, and only 46.3% of patients with chronic hepatitis B recognize the importance of antiviral therapy; most patients have high expectations of antiviral therapy, which is an important reason for poor adherence, and nearly half of patients discontinue their own medications, which is also an important reason for the occurrence of drug resistance in LAM treatment. Enhancing patient awareness and adherence education can help improve patients’ understanding of the importance of long-term treatment and reduce the occurrence of drug resistance. Avoidance of single-drug random sequences should be strictly avoided for single-drug random sequences of low resistance genetic barriers or cross-resistant drugs, such as LAM sequences with LdT or ADV. Single-drug random sequences can induce the risk of multidrug resistance mutations and cross-resistance. Another study showed that switching to ETV after LAM treatment resulted in poorer virologic response and susceptibility to drug resistance. To reduce the risk of drug resistance, the indications for treatment should be strictly controlled and unnecessary treatment should be avoided. 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, and immune tolerance with positive hepatitis B e antigen) should avoid treatment with nucleoside (acid) analogues. In addition, strengthening the education of medical personnel on the prevention and management of antiviral therapy resistance and avoiding irregular treatment situations, including single-drug random sequential therapy, frequent drug changes or drug additions within a short period of time, and unreasonable drug additions or drug changes after drug resistance, can help reduce the occurrence of drug resistance. At the same time, the positive interaction between academia, government departments and pharmaceutical companies is necessary to effectively reduce the irregular use of nucleoside (acid) analogues and the occurrence of drug resistance.