Work

Thromboembolic disease in HIV/AIDS: More attention is needed

Year: 2024

Type: article

Abstract: Human immunodeficiency virus (HIV) is a highly adaptable and rapidly evolving virus, and the current population of people infected with HIV and diagnosed with acquired immune deficiency syndrome (AIDS) continues to grow. Although the lifespan of HIV-infected people (PWH) has been extended through control with antiretroviral therapy (ART), however, as the aging of PWH increases, this population is prone to new complications, including thromboembolic disease (TED). TED has been recognized as one of the most common cardiovascular diseases among PWH. Thrombosis often causes vascular obstruction, blood stasis, and ischemic organ damage, leading to life-threatening illness or permanent disability, which can further affect the selection and use of ART drugs in PWH. Thrombosis has become a growing problem for HIV-infected individuals, and the burden on society will continue to increase as more and more people become infected. Therefore, we conclude the latest progress about causative factors and therapeutic interventions of HIV/TED to provide new ideas for in-depth clinical research and further optimize appropriate treatment options. Epidemiology of TED in HIV/AIDS patients. Studies have shown that about 85.6 million people have been infected with HIV to date. According to the United Nations Programme on HIV/AIDS (UNAIDS), as of 2022, there are approximately 39 million people living with HIV (PLWH) worldwide, of whom more than 60% have received ART treatment.[1] While PWH live longer, ART also increases the rate of arterial and venous thrombosis in PWH, compared with the general population. Studies have indicated that ART increased the overall risk of cardiovascular disease by 1.5–2.0 time, the risk of sudden cardiac death by 4.5 times. A meta-analysis of 80 studies by Shah et al[2] found that the risk ratio for cardiovascular disease was 2.16 (95% confidence interval [CI], 1.68–2.77) compared to individuals not infected with HIV. Previous epidemiological studies have reported a 2-fold to 10-fold increased risk of first-time venous thrombosis in PWH patients compared to age-matched controls. The high incidence of cardiovascular and thrombotic diseases in the context of HIV infection poses a great challenge to the healthcare systems of low- and middle-income countries around the world. Pathophysiology of HIV/AIDS-related thrombosis. The immune system activation and inflammatory response caused by HIV infection may be associated with the occurrence of TED. Studies have shown that HIV-infected individuals often have a chronic inflammatory state, which can lead to endothelial dysfunction, platelet activation, and abnormalities in the coagulation system, thereby increasing the risk of thrombus formation [Figure 1].Figure 1: Pathogenic factors affecting HIV/AIDS-related thrombosis. AIDS: Acquired immune deficiency syndrome; APS: Antiphospholipid antibody syndrome; HIV: Human immunodeficiency virus.Arterial thrombosis. Arterial thrombosis arises from the rupture of atherosclerotic plaque, and modern studies generally show that its formation begins with exposure to tissue factor (TF) at the rupture site. HIV infection causes activation of the immune system and an inflammatory response, which may promote the formation of blood clots in the arteries. The release of inflammatory mediators such as cytokines (such as tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and inflammatory cells (such as monocytes and macrophages)[3] can lead to endothelial dysfunction, platelet activation, and clotting system abnormalities, thereby increasing the risk of arterial thrombosis. Platelet activation plays a central role in the formation of arterial thrombosis. Platelets can engulf HIV virions, causing them to be activated in cell cultures, and this activation may increase the risk of thrombosis in PWH patients. Platelet activation is characterized by cell surface expression of CD62P, phosphatidylserine exposure, and the formation of platelet–T cell complexes, all of which have been shown to be significantly elevated in PLWH. Notably, PLWH was associated with an increased incidence of thrombocytopenia (17.9% [95% CI, 14.69–21.12%]) compared to the general population (0.0095%), especially in the absence of combination ART.[4] Venous thrombosis. Venous thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third leading cause of cardiovascular-related death after myocardial infarction and IS.[5] HIV infection may lead to inflammation in the veins, which increases the risk of venous thrombosis. Inflammation and endometrial damage can cause platelets and clotting factors to accumulate in the intravenous lumen and form thrombus. PLWH often presents with a deficiency of anticoagulant proteins, such as protein S, protein C, heparin cofactor II, and antithrombin.[6] However, few studies have been conducted to determine the cause of this deficiency, but opportunistic infections and malignancies associated with HIV disease have been proposed. A clear association between venous thrombosis and low CD4 T cell count in PLWH can be further demonstrated. Pathogenic Factors of HIV/AIDS-Related Thrombosis.HIV: As shown in Figure 2, HIV infection causes activation of the immune system and an inflammatory response, which may promote the formation of blood clots. The release of inflammatory mediators and cytokines induced by viral infection may lead to endothelial dysfunction, platelet activation, and coagulation system disorders, thereby increasing the risk of thrombosis HIV infection also leads to high blood viscosity, or reduced blood mobility. This high viscosity may increase the risk of thrombosis due to increased retention time of blood in the intravascular lumen.Figure 2: The possible mechanism of thrombus formation under HIV infection conditions. HIV: Human immunodeficiency virus; TF: Tissue factor; vWF: Von Willebrand factor.Abnormal immune system: Abnormalities in the immune system caused by HIV infection may also be associated with thrombosis. The continued activation of the immune system and the inflammatory response may lead to damage to the vascular endothelium, platelet activation, and disruption of the clotting system, thereby increasing the risk of thrombosis. Antiphospholipid antibody syndrome (APS) is an autoimmune disorder associated with thrombosis and repeated miscarriages. The incidence of APS may increase in HIV-infected people. This syndrome is associated with the production of anti-phospholipid antibodies, such as anti-cardiolipin antibodies and anti-beta-2 glycoprotein I antibodies, which may lead to an increase in thrombosis.[6] ART: ART is a common treatment for people with HIV/AIDS, but certain antiretroviral drugs may be associated with an increased risk of blood clots. For example, certain antiretroviral drugs (such as protease inhibitors) may cause abnormalities in lipid metabolism, thereby increasing the risk of arterial thrombosis.[7] In addition, certain medications may be associated with abnormal platelet function, further increasing the risk of thrombosis. Other risk factors: In addition to HIV/AIDS itself and treatment-related factors, other traditional thrombosis risk factors (such as age, genetic factors, obesity, smoking, high blood pressure, diabetes, etc.) may also play a role in HIV/AIDS patients. Some studies suggest that older and female patients may be more likely to develop blood clots. This may be related to age-related changes in blood vessel function, hormone levels, and increased platelet activity associated with estrogen.[8] Treatment status of HIV/TED.Drug treatment strategies: ART is the primary treatment for HIV infection and AIDS, and is also applicable to the treatment of HIV/TED. ART inhibits HIV replication and transmission by using a combination of multiple antiretroviral drugs. ART can help restore immune system function, lower viral load, and reduce virus-associated inflammatory responses, thereby reducing the risk of HIV/TED. In addition, anticoagulant therapy may be necessary for HIV/TED patients. Anticoagulant therapy involves the use of antiplatelet and anticoagulant drugs to prevent and treat thrombosis.[9] The specific treatment plan will be determined based on the patient’s condition and the severity of the clot. In addition to anticoagulant therapy, antiplatelet drugs can also be used to prevent and treat HIV/TED. Commonly used antiplatelet drugs include aspirin and clopidogrel. These drugs stop platelets from gathering and reduce the risk of blood clots forming. It is important to note that HIV/TED patients may face multiple complications at the same time, such as deep vein thrombosis, pulmonary hypertension, and heart failure.[10] For these complications, specific treatments may be required, such as anticoagulant therapy, thrombotic therapy, and surgery. Additional treatment and management may be required for these complications, and the choice of treatment will depend on the severity and overall condition of the patient. Preventive management measures: Prevention is one of the important measures to manage HIV/TED. This includes general prevention measures against thrombosis, such as maintaining good blood circulation, actively managing chronic diseases such as high blood pressure, diabetes, and hyperlipidemia, avoiding intravenous drug abuse, and maintaining a healthy lifestyle. HIV/TED is a chronic disease that requires long-term management and monitoring. This includes regular medical follow-up, blood tests, ultrasound, and other imaging tests to assess changes in clots and disease progression. In addition to medication, lifestyle changes are an important aspect of managing HIV/TED.[11] This includes quitting smoking, controlling weight, eating a balanced diet, exercising regularly, and managing chronic diseases. These measures can help reduce the risk of blood clots forming and improve overall health. In addition, the treatment of HIV/TED involves not only physical health but also mental health. Therefore, providing psychological support and counseling is essential for patients’ recovery and quality of life. This can include psychological counseling, support groups, and the use of community resources. Patient management: For HIV/TED patients, case management is a comprehensive approach designed to provide comprehensive treatment and support. This may involve multidisciplinary collaboration, including infectious disease specialists, cardiologists, thrombologists, mental health professionals, and social workers.[12] By coordinating and integrating expertise in different fields, comprehensive care and management of patients can be provided. New intervention strategies: In addition to medication, researchers are also exploring other intervention strategies to manage HIV/TED. This may include the use of specific hemofiltration techniques, thrombotic therapy, physical therapy, and surgical treatment. The choice of these interventions will depend on the patient’s specific circumstances and condition.[13] In addition, researchers are constantly working to develop new drugs to treat HIV/TED. These new drugs could include more effective antiretrovirals, anticoagulants, and new types of drugs that target blood clots.[14] These studies aim to improve treatment effectiveness, reduce side effects, and provide a better quality of life for HIV/TED patients. In addition to treating thrombosis itself, researchers are also exploring potential causes of HIV/TED. This could include studying inflammatory processes, immune system activation, and other biological processes associated with HIV.[15] With treatments that target these causes, HIV/TED can be managed more comprehensively and the risk of blood clots can be reduced. TED (HIV/TED) is one of the more common complications in HIV/AIDS patients. HIV infection and the impaired immune function and inflammatory response caused by HIV increase the risk of HIV/TED. Epidemiological studies of HIV/TED have shown that people living with HIV are at a higher risk of TED than the general population. In pathophysiology, HIV/AIDS-related immune dysfunction and inflammatory responses lead to platelet activation, endothelial damage, and coagulation system abnormalities that promote thrombosis. In addition, the direct action of the HIV itself may also be involved in the mechanism of thrombosis. Risk factors, including high viral load, low CD4+ T lymphocyte count, inadequate ART, age, smoking, obesity, and chronic inflammation, are all associated with the development of HIV/TED. Current treatment strategies include anticoagulant therapy, antiplatelet therapy, and management of associated complications. However, treatment is still individualized and needs to be tailored to the patient’s specific situation and condition. There is a lack of sufficient clinical attention to HIV-associated thrombosis, and the 2020 ASH Guidelines for antithrombotic and thrombolytic therapy make no mention of HIV-infected patients. Therefore, future research is urgently needed to explore new therapeutic approaches and intervention strategies to improve the quality of life and prognosis of HIV/TED patients. Given the high morbidity and mortality of thrombotic diseases, more research is needed to understand the underlying mechanisms driving PWH with thrombosis in order to create better therapies to reduce chronic inflammation in PLWH. These therapies could potentially reduce the rate of atherosclerosis, cardiovascular disease, and thrombosis in PLWH, thereby reducing the overall mortality rate in this population. Funding This study was supported by grants from Shenzhen Third People’s Hospital project (Nos. 22240G1013, 22250G1013), HUI LAN Public Welfare (No. 23250H1003), Henan Clinical Research Center of Infectious Diseases (AIDS) (Affiliated Infectious Diseases Hospital of Zhengzhou University, and Henan Infectious Diseases Hospital) 2024 Open Subjects (No. KFKT202402). Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003358