With the development of AIDS cocktail therapy, the generation of immune reconstitution has improved the life expectancy and quality of life of patients, but then various drug-related complications have come to the fore, among which lactic acidosis is one of its important long-term complications. Early identification and early diagnosis and treatment are the key factors to avoid serious lactic acidosis, and I hope this article can give you some help.
1. The incidence of lactic acidosis in long-term anti-HIV drugs: According to the clinical survey: the overall incidence of lactic acidosis during HAART is 10.6 cases/1000 person-years, and there is 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. In addition, a South African survey of 891 HIV(+) patients on HAART (3TC + d4T + 1NNRTI) for 18 months showed an incidence of lactic acidosis of 19 cases per 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 given prolonged nucleoside antiviral therapy can range from 8% to 20%, depending on factors such as the definition of lactic acidosis itself, the duration of treatment with NRTIs, the use of specific drugs, and demographics. Most studies have shown that the incidence of symptomatic hyperlactatemia in patients receiving NRTI is 0.5-1%.
2. Pathophysiological mechanism and clinical characteristics: The process of glucose metabolism to generate water and CO2 under aerobic conditions becomes aerobic oxidation, while under anaerobic conditions or linear steric injury glucose is broken down into pyruvate and then lactate is generated under the catalytic action of lactate dehydrogenase, which is the end product of glycolysis. Hyperlactatemia is defined as a blood lactate level of 2 mmol/L or more. It can be asymptomatic or have mild symptoms or even occur as a severe and 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 altered oxygen metabolism induced mitochondrial damage by nucleoside analogs and the individual’s own presence of 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 mitochondrial DNA deprivation and reduced synthesis of at least one protein required for proper mitochondrial function, resulting in mitochondrial malfunction and lactic acidosis (3). 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. NRTIs can also cause fat accumulation in the liver, resulting in impaired liver function and inability to efficiently break down lactate, leading to increased lactate levels in the blood. The natural history of hyperlactatemia is still unclear. Whether asymptomatic patients with hyperlactatemia will necessarily progress to lactic acidosis after continued use of NRTIs requires further scientific study. The onset of lactic acidosis symptoms can be acute or subacute, with subacute onset usually being more common. In the early stages of lactic acidosis, patients often have symptoms that are difficult to categorize and may consist only of gastrointestinal discomfort, bloating, diarrhea, and sudden weight loss. In severe cases, weakness of the extremities, muscle pain, liver pain or enlargement, abnormal liver function, acute pancreatitis, and decompensated metabolic acidosis occur. The possibility of lactic acidosis needs to be considered in patients who were previously stable and then developed the above symptoms rapidly within a few days.
Lactic acidosis is considered when the blood lactate is 3 5 mmol/l and PH £ 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 3 5 mmol/l with corresponding clinical symptoms; or blood lactate is 3 10 mmol/l with or without clinical symptoms. Other laboratory indicators that can be abnormal include elevated CPK (creatine kinase), LDH (lactate dehydrogenase), AMY (amylase), AST (glutamate aminotransferase), and AG (anion gap), as well as hypoproteinemia, decreased PH and HCO3 (bicarbonate) ion concentrations, CT scans, ultrasounds, and liver biopsies suggesting hepatocellular steatosis. Lactic acidosis rarely occurs when blood lactate is <5 mmol/L. 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 tubes should be used; no tourniquet should be used when drawing blood; specimens should be kept refrigerated and transported to the destination within 4 hours; no strenuous activity for 24 hours before drawing blood to ensure adequate oxygen supply, etc. Usually the level of blood lactate 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 course 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 lactic acidosis signs and symptoms, and take timely measures to reduce mortality. Clinical practice can guide us that we should be alert to certain signs of lactic acidosis: the following symptoms in patients being treated with NRTIs: including unexplained dyspnea, nausea, abdominal pain, wasting and/or liver failure; unexplained laboratory test abnormalities: elevated anion gap, hypoproteinemia, decreased HCO3, etc.; special populations: pregnant women currently taking NRTIs, those who have had lactic acid The NRTI has been discontinued for acidosis and is currently being taken again. 3.Treatment and prognosis of lactic acidosis (and CVVH to correct the pathophysiological mechanism of acidosis): The above is the pathophysiological mechanism of hyperlactatemia and lactic acidosis, and we should understand that different treatment plans should be made according to different blood lactate levels and different clinical characteristics of patients. In general, those with blood lactate levels below 5 mmol/L do not require special treatment. If conditions permit, stavudine or desoxycreatin can be replaced with ABC/TDF. 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. If necessary, respiratory support and continuous blood purification. There are no results of controlled trials on the efficacy and safety of the above drugs. L-carnitine is a co-factor of mitochondrial aerobic metabolism, inhibits apoptosis and also reverses mitochondrial toxicity due to NRTIs. NRTIs-associated lactic acidosis was successfully treated in a HIV-infected patient with blood lactate >10 mmol/l with an early treatment regimen that included levocarnitine.
Severe lactic acidosis requires not only aggressive medical drug therapy, but also hemodialysis to assist in the correction of severe metabolic acidosis and the removal of excess lactic acid produced by the body. In a retrospective analysis of 25 cases of severe lactic acidosis, 25 patients were divided into two groups: the conventional group (13 cases) received conventional treatment, including allopathic treatment, maintenance of water and electrolyte balance, and 5% sodium bicarbonate intravenous drip to correct acidosis. The changes of blood lactate and blood pH, the effect of CVVH in removing lactate, and the mortality rate of patients were observed. All patients were treated with a central venous line (single needle, double lumen) as vascular access. CVVH was performed continuously 24 hours a day. 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) p="">0.05), but the patients in the CVVH group had a significantly higher APACHE II score. In this group of patients with severe lactic acidosis treated with CVVH, it was observed that the rate of decrease in blood lactate and increase in blood pH was faster and smoother than that of conventional treatment, and although there was no significant difference in the mortality rate between the two groups, the severity of the disease was significantly higher in the CVVH group than in the conventional treatment group. In the treatment of severe lactic acidosis with CVVH, we believe that its therapeutic mechanism is manifested in two aspects. First, the most fundamental treatment for lactic acidosis is the treatment of the cause, 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 the tissue hypoxia is corrected, and this effect of CVVH has been proved by many studies. The effect of CVVH on lactic acid removal can improve and maintain the body’s internal environment, thus gaining time for the treatment of the primary disease. In conclusion, CVVH treatment can improve the internal environment of patients with severe lactic acidosis and maintain the acid-base balance in order to save patients’ lives based on conventional medical drug therapy.
In the treatment of severe lactic acidosis, for patients with respiratory failure, the application of mechanical ventilation can increase the partial pressure of arterial blood oxygen, increase tissue oxygen supply, reduce lactic acid production, and accelerate lactic acid metabolism.
The lactic acidosis symptoms may continue or worsen at the beginning after discontinuation of the drug, and the patient needs a long time to recover. The renewal cycle of linear DNA is 4.5-8 weeks, and the patient needs 4-28 weeks to recover from the 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 achieved, 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.). Hyperlactatemia was relieved after d4T replacement with ABC. It is emphasized here that even if the patient can safely apply other NRTIs, clinicians should perform strict regular lactate monitoring in this group of patients. Since the prognosis of a patient with lactic acidosis cannot be discerned from the patient’s clinical presentation, how does one go about defining a threshold value that would alert clinicians to give extra attention to the occurrence of lactic acidosis in a patient? They applied a statistically derived predictive value of 9 mmol/l for blood lactate for possible risk of patient 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 attention paid to the problem by the clinician. The prognosis of lactic acidosis is severe. In general, blood lactate levels are positively correlated with the severity of the condition. The longer the duration of high lactate levels without significant reduction after the above mentioned treatment, the worse the prognosis. By multivariate analysis, the only variable associated with mortality is blood lactate >10 mmol/l. Most authors do not recommend routine testing of lactate levels in HIV-infected patients treated with NRTIs. Asymptomatic, mildly elevated blood lactate and normal bicarbonate patients who subsequently develop lactic acidosis are rare. In contrast, blood lactate levels should be monitored in those with symptoms of lactic acidosis and corresponding abnormal laboratory tests, as well as in pregnant women treated with NRTIs. After full recovery from lactic acidosis has occurred, it is highly recommended that blood lactate levels be rechecked every month for at least 3 months after the start of treatment if other drugs in NRTIs are reapplied.