Currently, five nucleoside (acid) analogues [NA, lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LDT), tenofovir (TDF)] have been approved for the antiviral treatment of chronic hepatitis B (CHB), and there have been more clinical studies about their efficacy and drug resistance in the treatment of CHB. The safety of the drug has also received increasing attention from clinicians as the duration of patient treatment has increased. The efficacy, risk of drug resistance, patient compliance and safety of antiviral therapy for CHB are four key factors in the long-term management of CHB patients, of which safety is an issue that requires special attention: ① All NA are generally well tolerated, but the safety of long-term therapy remains to be proven; ② Before treatment, the risk of adverse events must be measured against the benefits of treatment; ③ Drugs in treatment Safety issues are closely related to patient population characteristics and adverse drug reactions. Factors that must be considered in the long-term treatment of CHB include factors that affect treatment selection, efficacy and safety, such as patient factors, including age, gender, race, smoking and alcohol habits, pregnancy, medication adherence, and drug combination; disease factors, including the presence of overlapping infections, severe liver disease, cardiovascular disease risk, and other co-morbidities. and other concomitant diseases. Therefore, long-term treatment of CHB requires consideration of multiple influencing factors. Common Adverse Events in NA Currently, common adverse events in NA include dizziness, gastrointestinal symptoms, headache and discomfort, as well as rash, elevated serum creatine kinase (CK), abnormal creatinine clearance (CrCl), and elevated amylase and lipase. In general, NA is well tolerated by patients with a low rate of treatment discontinuation, but safety data vary for each drug (e.g., in renal insufficiency, myopathy, muscle pain, etc.). In clinical practice, physicians need to analyze the case in context. Overall patient health status that must be taken into account for long-term treatment Patients with CHB must pay attention to the overall health status of the patient in order to achieve long-term treatment, otherwise patients may have to discontinue treatment due to intolerance in treatment, or even more serious health impairment. In the long-term treatment of CHB patients, special attention should be paid to the health status of patients’ vital organs such as kidneys, heart and bones: CHB infection is closely associated with decreased bone density, and osteoporosis is a common symptom in patients with CHB cirrhosis; in the Asian American population, CHB infection is closely associated with the development of type 2 diabetes, and in patients with type 2 diabetes, CHB infection increases the risk of end-stage kidney disease in patients. Chronic viral diseases such as CHB can lead to kidney injury and renal dysfunction; drugs with nephrotoxic properties may increase the risk of kidney injury in patients with CHB. Mitochondrial toxicity of NA All NA instructions contain a black box warning about mitochondrial toxicity; clinical manifestations associated with NA-induced mitochondrial toxicity include lactic acidosis, fat redistribution, hepatic steatosis, acute pancreatitis, renal proximal tubular disorders, myopathy, peripheral neuropathy, hematologic disorders, and cardiomyopathy. Before NA long-term treatment, patients must be alerted to the risk of kidney injury The molecular structure of nucleoside analogs is composed of pentose and base, and that of nucleotide analogs is composed of pentose, base and phosphate. Currently, there are five nucleoside and nucleotide analogues approved for the treatment of CHB, of which LAM, LDT and ETV belong to the nucleoside analogues and ADV and TDF belong to the nucleotide analogues. The different molecular structures of drugs lead to different molecular weight sizes, which in turn lead to different renal clearance of drugs. as the molecular weight increases, the rate of drug filtration in the kidney decreases. the mode of NA excretion in the kidney includes glomerular filtration and tubular secretion. The mechanism is related to drug-induced mitochondrial toxicity such as enlargement and deformation of renal tubular mitochondria and abnormal energy metabolism, and abnormal transport protein function leading to decreased trans-tubular secretion and increased tubular aggregation. The mechanism is related to the decrease in drug secretion through the tubules and the increase in tubular aggregation due to abnormal transport protein function. In the long-term treatment of CHB, NA can have certain effects on renal function, especially nucleotides, which are more likely to lead to renal dysfunction and renal injury due to the relatively high drug concentration in the renal proximal tubule during renal excretion. To avoid such adverse events, care should be taken to identify potential risk factors for nephrotoxicity, such as diabetes mellitus, atherosclerosis and elderly patients. The drug dose and dosing interval should be adjusted for patients who develop renal insufficiency during treatment. NA Long-term treatment, changes in bone metabolic indexes should be paid attention to In 2009, Rui (Re) et al. reported an investigative study on the relationship between viral hepatitis and bone metabolism among human immunodeficiency virus (HIV) infected patients, a total of 1237 HIV-infected patients were included, 625 of whom were co-infected with viral hepatitis, and multiple regression analysis showed that after excluding confounding factors, viral hepatitis among HIV-infected patients was a female The multiple regression analysis showed that viral hepatitis was a high risk factor for the development of decreased bone mineral density among HIV-infected women, excluding confounding factors. Schiefke et al. found altered bone metabolism in patients with hepatitis B or C. More than 50% of patients had osteoporosis. Osteoporosis is more common in patients with post-hepatitis cirrhosis. In recent years, as antiviral therapy for CHB continues to progress, there has been increasing concern about bone metabolism in patients. Fanconi syndrome (FCS) is a group of syndromes caused by hereditary or acquired abnormalities of proximal tubular function. The reabsorption of phosphate, magnesium, potassium, sodium, glucose, amino acids, uric acid and bicarbonate by the proximal tubule of the kidney is impaired, resulting in the excretion of these substances through the urine, with clinical manifestations including hyperphosphaturia, bone disease, proteinuria, amino aciduria and acidosis. Recent reports have shown cases of decreased bone mineral density and Fanconi syndrome during NA treatment. It remains to be seen whether bone metabolism indicators must be included in CHB treatment monitoring or related management. Other safety issues of NA therapy Lactic acidosis has been shown to correlate with the severity of liver disease during NA therapy, but the occurrence of lactic acidosis during decompensated CHB therapy is not associated with antiviral therapy. The American Association for the Study of Liver Diseases guidelines recommend that patients with impending or significant hepatic decompensation should be treated with ETV or TDF (ⅠA), and patients treated with nucleoside analogs for the first time may also be treated with LDT, LAM, or ADV (ⅠB), with monitoring of renal function and lactic acidosis during treatment, especially in patients with Model for End-Stage Liver Disease (MELD) scores >20 (ⅢA). Elevated creatine kinase CK catalyzes the phosphorylation of creatine with the participation of adenosine triphosphate (ATP) to produce ATP (a source of energy supply for muscles) and creatine phosphate; CK is distributed in skeletal muscle, cardiac muscle, brain, thyroid, lung tissue, and gastrointestinal smooth muscle, with the highest content in skeletal muscle, followed by cardiac muscle, then brain and gastrointestinal smooth muscle. Therefore, elevated serum CK is generally indicative of increased cell permeability or tissue cell destruction in CK-containing tissues. Some studies have reported elevated CK in some patients treated with NA. Myopathy is defined as persistent unexplained muscle pain and/or muscle weakness accompanied by elevated CK values, and should be considered in any patient presenting with diffuse muscle pain, muscle tenderness, or muscle weakness. If myopathy is suspected, related drug therapy should be suspended, while if myopathy is diagnosed, related drug therapy should be discontinued. Efficacy, resistance, and safety are three key factors in achieving the long-term goals of nucleoside (acid) analogs for CHB, and clinicians should consider all of these factors when choosing an antiviral regimen for CHB. Nucleoside (acid) antiviral therapy can have certain effects on renal function, which may be one of the independent factors affecting the decrease of bone mineral density; lactic acidosis during CHB antiviral therapy is related to the severity of liver disease, and patients with severe liver disease need to pay attention to the potential risk of lactic acidosis when using nucleoside (acid) antiviral therapy. Summary China’s guidelines for the prevention and treatment of chronic hepatitis B recommend careful questioning of relevant medical history prior to treatment to reduce the risk. Patients with significantly elevated serum creatinine, CK or lactate dehydrogenase with corresponding clinical manifestations such as deterioration of general condition, obvious myalgia and muscle weakness during treatment should be closely observed, and once the diagnosis of uremia, myositis, rhabdomyolysis or lactic acidosis is confirmed, the drug should be discontinued or changed to other drugs in a timely manner, and appropriate treatment should be actively given.