There are currently two classes of antiviral drugs for chronic hepatitis B: long-acting interferons, which require injections, and nucleoside analogues, which are taken orally. The former have a better chance of achieving e antigen serologic conversion and surface antigen clearance and can be discontinued long-term after 48 weeks of effective treatment, although interferons require injectable therapy and many patients have significant concerns about local or systemic adverse effects during treatment. Unlike interferon, nucleoside analogs are more convenient to take orally and have fewer adverse effects overall, making them more acceptable to patients. However, nucleoside therapy also has its limitations: long-term treatment is required, and as nucleoside use extends, a variety of problems may arise. There are 2 main problems facing long-term nucleoside therapy: drug resistance and adverse effects. The mechanism of action of nucleosides is to directly inhibit hepatitis B virus replication, the specific mechanism is more complex, in short, the hepatitis B virus is a long chain of deoxyribonucleotides, it will continue to replicate with the help of polymerase, nucleoside drugs can block the role of this enzyme, thereby inhibiting viral replication. This action can work well when the drug is first taken, but under the pressure of the drug, the hepatitis B virus will gradually mutate and escape the effect of the drug on the polymerase, that is, drug-resistant mutation will occur. Obviously, due to this mechanism, drug resistance is difficult to avoid, although there are differences in the incidence of drug resistance among different nucleoside analogues, of which lamivudine, which is currently the most widely used, has the highest likelihood ratio of drug resistance. Once resistance mutation occurs, the otherwise effective nucleoside therapy fails, and both transaminases and viral levels will be raised again, potentially causing accelerated disease progression. In order to avoid disease progression after drug-resistant mutation, it is important to insist on follow-up after taking oral drugs, to detect problems early, and to adopt a combination therapy or drug change regimen, and when changing the treatment regimen, care should be taken to avoid more complicated problems such as cross-resistance and multiple drug resistance. The safety of long-term nucleoside therapy should not be taken lightly either. Although the safety of oral nucleosides is generally good, it can become an issue as the duration of treatment increases. Nucleosides are mainly excreted from the kidneys, therefore, serum creatinine levels, renal function and other indicators should be monitored after nucleoside therapy. Some studies have shown that Adefovir is used continuously for 4-5 years and 3% develop nephrotoxicity. In addition, adefovir and tenofovir have the potential to cause a decrease in bone density in patients, and telbivudine can cause transverse myelopathy. In conclusion, nucleoside analogues require long-term treatment, and after choosing this treatment option, one should be patient and adhere to the medication on the one hand, and do regular review on the other hand, to detect problems early and deal with them as early as possible to guarantee the efficacy of treatment.