Since the introduction of HAART for the treatment of AIDS in 1996, AIDS-related morbidity and mortality have been greatly reduced. However, the toxic side effects of long-term drug use have become a prominent and sometimes life-threatening problem, severely limiting its use in clinical practice. Two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with any one of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PI) are the commonly used HAART regimens for AIDS patients in China. NRTIs can cause hyperlactatemia or lactic acidosis, which has been reported in foreign literature. Although the incidence of lactic acidosis is low, once it occurs, the mortality rate is still high even if the relevant drugs are discontinued. Therefore, it is helpful for medical personnel to master the knowledge related to lactic acidosis caused by NRTIs, to detect early patients with hyperlactatemia in time, and to take timely measures to reduce the incidence of serious adverse reactions during HAART treatment in AIDS patients and to maximize the life of patients. 1. Incidence of lactic acidosis in patients receiving long-term nucleoside analogues: A retrospective study showed that follow-up of 1735 AIDS patients (1093 women) treated with HAART from April 2004 to August 2005 revealed that 22 women and 1 man developed lactic acidosis. The overall incidence was 10.6 cases/1000 person-years, with a significant difference between men and women, with a female incidence of 16.1 cases/1000 person-years and a male incidence of 1.2 cases/1000 person-years. Hyperlactatemia also occurred in 37 women and 7 men, with an incidence of 20.2 cases/1000 person-years for all, while the incidence differed by gender (8.7 cases/1000 person-years and 27 cases/1000 person-years for men and women, respectively). Obesity may also be a high risk factor, with primary patients with a body mass index greater than 30 accounting for 25% of all lactic acidosis and hyperlactatemia described above. Almost all patients who eventually developed lactic acidosis or hyperlactatemia were treated with d4T. 56 patients who restarted HAART and switched from the original regimen of d4T to AZT had no recurrences at 4.6 years of follow-up. In addition, a South African study showed an incidence of lactic acidosis after 18 months of HAART (3TC + d4T + 1NNRTI) of 19 cases¤1000 person-years, a mean duration of administration of 7.5 months, a mean peak blood lactate of 9.3 mmol/l, and a mortality rate of 29%. The overall mortality rate of lactic acidosis is 30-60%, and when blood lactate > 10 mmol/l, the mortality rate is nearly 100%. The incidence of asymptomatic or mildly symptomatic hyperlactatemia in patients on long-term nucleoside antiviral therapy is 8% – 20%, depending on a number of factors such as the definition of lactic acidosis itself, the duration of treatment with NRTIs, the application of specific drugs, and demographics. Most studies have shown that the incidence of symptomatic hyperlactatemia in patients receiving NRTI is 0.5-1%. Nucleoside analogs are toxic to mitochondria in the order of d4T/ddi>d4T>ddI>AZT. Other NRTIs such as 3TC (lamivudine), FTC (emtricitabine), TDF (tenofovir), and ABC (abacavir) rarely cause it. Risk factors for the development of lactic acidosis include: female, pregnancy, obesity, ddi and d4T combination, ribavirin or hydroxyurea use. 2, pathogenesis of lactic acidosis in AIDS patients: the process of glucose metabolism to produce water and CO2 under aerobic conditions is called aerobic oxidation, under anaerobic conditions or mitochondrial damage then glucose is broken down into pyruvate and then lactate is generated under the catalytic action of lactate dehydrogenase, lactate is the end product of glycolysis. Hyperlactatemia is defined as a blood lactate level of 2 mmol/L or more. It can present as asymptomatic, mildly symptomatic or even occur as a severe fatal lactic acidosis. Lactic acidosis is generally diagnosed when the blood lactate level is greater than 5 mmol/L and the patient presents with the clinical features and biochemical indicators of metabolic acidosis. The causative mechanism is not fully understood, and it is speculated that it may be related to factors such as nucleoside analogs that alter oxygen metabolism and induce mitochondrial damage, the individual’s own existing liver damage or nutritional disorders (e.g., lack of vitamin B2 and levocarnitine). NRTIs damage mitochondria because they inhibit mitochondrial DNA polymerase g. This inhibition leads to a lack of mitochondrial DNA and a decrease in protein synthesis that maintains normal mitochondrial function, resulting in abnormal mitochondrial function and lactic acidosis. NRTIs can also impair the b-oxidation cycle, preventing long-chain fatty acids from entering the mitochondria and accumulating in the cytoplasm, increasing glycolysis and subsequently lactate, leading to an imbalance in the lactate/pyruvate ratio. In addition, it has been reported in the literature that NRTIs have a pro-apoptotic effect, and mitochondrial apoptosis promotes increased lactate. NRTIs also cause hepatic fat accumulation, which impairs liver function and prevents effective lactate breakdown, resulting in increased blood lactate levels. The natural history of hyperlactatemia remains unclear, and further scientific studies are needed to determine whether asymptomatic patients with hyperlactatemia will definitely progress to lactic acidosis after continued use of NRTIs. 3. Clinical characteristics and diagnosis of lactic acidosis: symptoms of lactic acidosis can be manifested as either acute or subacute onset, and usually subacute is more common. At the beginning of lactic acidosis, patients often have symptoms that are difficult to categorize, such as gastrointestinal discomfort, abdominal distension, diarrhea, and sudden weight loss; in severe cases, weakness of limbs, muscle pain, liver pain or enlargement, abnormal liver function, acute pancreatitis, and decompensated metabolic acidosis. The possibility of lactic acidosis needs to be considered in patients who previously had a stable condition and then developed the above symptoms rapidly within a few days. Lactic acidosis is considered when the blood lactate is 5 mmol/l with a pH of 7.35, while ensuring proper specimen collection. It has been reported in the literature that in AIDS patients treated with NRTIs, lactic acidosis is usually asymptomatic when blood lactate is between 2.0-5.0 mmol/l and is referred to as asymptomatic hyperlactatemia; lactic acidosis is diagnosed when blood lactate is 5 mmol/l with corresponding clinical symptoms; or when blood lactate is 10 mmol/l with or without clinical symptoms. Other laboratory indicators that can be abnormal include abnormally elevated CPK (creatine kinase), LDH (lactate dehydrogenase), AMY (amylase), AST (glutamate aminotransferase), AG (anion gap), hypoproteinemia, decreased pH, decreased HCO3 (bicarbonate) ion concentration, and hepatocellular steatosis. Lactic acidosis rarely occurs when blood lactate is <5 mmol/L (10). However, clinicians should pay some attention to patients with blood lactate levels of 2-5 mmol/L without clinical symptoms. For the accuracy and reliability of blood lactate level testing, specimen collection is required to be very strict: fluoride oxalate blood collection tubes should be used; no tourniquet should be used during blood draw; specimens should be kept refrigerated and transported to the destination within 4 hours; no strenuous activity for 24 hours before blood draw to ensure adequate oxygen supply, etc. Usually the blood lactate level is correlated with the severity of the disease: according to statistics, 0-2mmol/L is the normal level, 5-10mmol/L has a mortality rate of 7%, 10-15mmol/L has a mortality rate of more than 30%, and more than 15mmol/L has a mortality rate of more than 60%. Therefore, in the process of clinical practice, we should actively take medical history, carefully examine the body, analyze the characteristics of the disease, strive for timely and early detection of patients with signs of lactic acidosis, and take timely measures to reduce mortality. In clinical practice, patients receiving NRTIs should be alerted to lactic acidosis when the following symptoms occur: unexplained dyspnea, nausea, abdominal pain, wasting and/or liver failure; unexplained abnormal laboratory tests: elevated anion gap, hypoproteinemia, decreased HCO3, etc.; special populations: pregnant women currently taking NRTIs, and those who have previously suffered from lactic acidosis and have stopped taking NRTIs and are currently taking them again. Those who are currently taking it again. 4. Treatment and prognosis of lactic acidosis: We should make different treatment plans according to different blood lactate levels and clinical characteristics of patients. Generally speaking, patients with blood lactate levels below 5 mmol/L do not need special treatment, and monitoring of blood lactate levels and symptoms is sufficient. If conditions allow, stavudine or desoxycreatin can be replaced with ABC/TDF, etc. Most investigators now believe that antiretroviral therapy needs to be discontinued immediately for any HIV patient on HAART with blood lactate >5 mmol/L with appropriate clinical symptoms, or when blood lactate is >10 mmol/L. In addition, glucose intake should be restricted, acid correction with appropriate sedative sodium bicarbonate, vitamin complexes such as levocarnitine 1g Tid, riboflavin (vit B2) 50mg po qd, thiamine (vit B1) 100mg po qd, high dose vitamin C 1-3g/d and coenzyme Q10 100mg po qd applied, respiratory support and continuous blood purification if necessary. The efficacy and safety of the above drugs have not been tested in controlled trials, but L-carnitine is a cofactor of mitochondrial aerobic metabolism, which not only inhibits apoptosis but also reverses mitochondrial toxicity due to NRTIs. . Severe lactic acidosis requires not only aggressive medical medication but also hemodialysis to assist in the correction of severe metabolic acidosis and the removal of excess lactic acid produced by the body. The 25 patients were divided into two groups: the conventional group (13 patients) received conventional treatment, including allopathic treatment, maintenance of water and electrolyte balance, and 5% sodium bicarbonate intravenous drip to correct acidosis; the CVVH group (12 patients) applied CVVH on the basis of conventional treatment, and the changes of blood lactate and blood pH before and after treatment were observed and analyzed. The treatment parameters of CVVH were: blood flow 160-180 ml/min after replacement, replacement rate 2,000 ml/h. Normal heparin anticoagulation, the first dose of 10 mg, 6 mg per hour maintenance. The formula of replacement fluid at the beginning of treatment was as follows: 3,000 ml of physiological saline, 500 ml of 5% glucose, 335 ml of water for injection, 150 ml of 5% sodium bicarbonate, 12 ml of 10% potassium chloride, 3 ml of 25% magnesium sulfate. 10-20 ml of 10% calcium gluconate was administered in a separate tube every hour. mmol/L. Central venous line (single needle, double lumen) was used as vascular access in all patients. CVVH was performed continuously 24 hours a day. After the initial correction of acidosis and the pH of arterial blood rose to 7.20, the replacement fluid formula was changed to 2,800 ml of physiological saline, 500 ml of 5% dextrose, 450 ml of water for injection, 235 ml of 5% sodium bicarbonate, 12 ml of 10% potassium chloride, and 3 ml of 25% magnesium sulfate, with a HCO-3 concentration of 35 mmol/L and sodium of 143 mmol/L. There was a significant difference in the rate of decrease in blood lactate and increase in blood pH between the two groups (P < 0.05), and the CVVH group was better than the conventional group; the level of lactate in the CVVH filtrate was basically the same as that of blood lactate at the same time; there was no significant difference in mortality between the two groups (P > 0.05), but the APACHE II score was significantly higher in the CVVH group. Compared with conventional treatment, the rate of decrease in blood lactate level and increase in blood pH in CVVH-treated patients was rapid and steady, and although there was no significant difference in the mortality rate between the two groups, the severity of patients in the CVVH group was significantly higher than that in the conventional treatment group. Therefore, CVVH can be used for the treatment of severe lactic acidosis, and the treatment effect is better than conventional treatment. The use of continuous hemofiltration in the treatment of lactic acidosis has been reported overseas and has achieved good therapeutic effects. We believe that the treatment mechanism of CVVH for severe lactic acidosis is manifested in two aspects: First, the most fundamental treatment for lactic acidosis is etiological treatment, such as correcting shock and improving circulation. CVVH can improve the patient’s internal environment, remove many inflammatory mediators in the body, improve the microcirculation, so that tissue hypoxia is corrected, this mechanism of CVVH has been proved by many studies. Another mechanism of action of CVVH is that it can directly remove excess lactic acid from the body and directly reduce acidosis, thus maintaining the stability of the internal environment. The effect of CVVH in removing lactic acid is to improve and maintain the body’s internal environment, and to gain time for the treatment of the primary disease. At the beginning of CVVH treatment, the concentration of HCO-3 in the replacement fluid is set at 20 mmol/L, which aims to prevent the patient’s acidosis from being corrected too quickly and avoid the leftward shift of the hemoglobin oxygen dissociation curve, which increases the affinity of hemoglobin for oxygen and reduces the release of oxygen to the surrounding tissues, thus aggravating the tissue hypoxia. After the acidosis is initially corrected and the arterial blood pH rises to 7.20, the HCO-3 concentration in the replacement fluid is increased to 35 mmol/L, so that the internal environment finally reaches a stable equilibrium. In conclusion, CVVH treatment can improve the internal environment and maintain the acid-base balance of patients with severe lactic acidosis, and can improve the prognosis of patients with severe lactic acidosis by removing lactic acid from the blood in addition to conventional medical treatment. For patients with respiratory failure, mechanical ventilation can increase the partial pressure of arterial oxygen, increase tissue oxygen supply, reduce the production of lactic acid and accelerate the metabolism of lactic acid, and at the same time, mechanical ventilation can increase the excretion of excessive CO2 produced by rapid input of large amounts of sodium bicarbonate, maintain acid-base balance and improve the prognosis of patients. Symptoms of lactic acidosis may continue or worsen after discontinuation of the drug, and patients need a long time to recover. The renewal cycle of mitochondrial DNA is 4.5-8 weeks, and patients need 4-28 weeks to recover from clinical symptoms. As long as the patient’s life is not threatened by HIV at that time, the discontinuation period is as long as possible until the symptoms disappear and the blood lactate level falls into the normal range. A recent study showed that the average time to symptom resolution after discontinuation was 62 days (7-76 days). If full recovery is possible, patients can take HAART again, but absolutely avoid previously used NRTIs and preferably use NNRTIs and PI-based drugs, such as 1 augmented PI or 1 NNRTI + 2 NRTIs known to be less toxic to mitochondria (e.g., ABC, TDF, LAM, FTC, etc.), with remission of hyperlactatemia after replacement of d4T with ABC . It is emphasized here that even if the patient can safely apply other NRTIs, clinicians should perform regular and rigorous lactate monitoring in this group of patients. The prognosis of patients with lactic acidosis cannot be discerned from the clinical presentation, so how can a threshold be defined to alert clinicians to give extra attention to the occurrence of lactic acidosis?The study by Cote HCF et al. suggests that the first blood lactate level after admission is of clinical importance. They applied a statistically derived predictive value of 9 mmol/l for blood lactate for possible risk of death due to hyperlactatemia, with a positive predictive value of 82% and a negative predictive value of 94.5%, with high sensitivity and specificity. The overall prognosis of lactic acidosis induced by NRTIs depends on the cause of the lactic acidosis and the importance that clinicians attach to this problem. In general the level of blood lactate is positively correlated with the severity of the condition. High lactate levels that do not decrease significantly after the above-mentioned treatments and that persist for a longer period of time are indicative of a worse prognosis. By multivariate analysis, the only variable associated with mortality was blood lactate >10 mmol/l. Most authors do not recommend routine testing of lactate levels in HIV-infected patients treated with NRTIs. Patients with asymptomatic, mildly elevated blood lactate and normal bicarbonate subsequently develop lactic acidosis are rare. In contrast, blood lactate levels are monitored in those with symptoms of lactic acidosis and corresponding abnormal laboratory tests, and in pregnant women treated with NRTIs. After complete recovery from lactic acidosis, it is strongly recommended that blood lactate levels be rechecked every month for at least 3 months after the start of treatment if other drugs of NRTIs are used again. 5. Conclusion The widespread use of HAART has significantly reduced the morbidity and mortality rate and greatly extended the survival period of AIDS patients. However, the toxic side effects of long-term drug use, especially lactic acidosis, have become prominent and even life-threatening to patients, which is a serious problem faced by clinicians and patients today. If a patient survives lactic acidosis, he or she will have to go through a “drug holiday” until the blood lactate is normalized before reapplying other NRTIs, causing the increased CD4 level to drop progressively during the “drug holiday”. At the same time, the occurrence of lactic acidosis poses a greater challenge for the patient in choosing the next antiviral drug. There is no definitive standard of care for lactic acidosis, and even timely discontinuation of medications, mechanical ventilation, intensive supportive therapy, and acid correction are sometimes not sufficient, and continuous blood purification can improve the prognosis of patients. As a clinician, when HIV-infected patients taking HAART therapy with drugs containing NRTIs have a rapid worsening of their condition within a few days in a previously stable condition, gastrointestinal discomfort, weakness of the limbs, muscle pain, abdominal pain, and liver pain or enlargement need to consider the possibility of lactic acidosis.