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    Home > Active Ingredient News > Infection > How to manage HIV-related cognitive impairment? Experts say so!

    How to manage HIV-related cognitive impairment? Experts say so!

    • Last Update: 2021-04-28
    • Source: Internet
    • Author: User
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    *The professional part involved in this article is only for medical professionals to read for reference.
    On March 25, the China AIDS webinar is waiting for you.

    In the first decade of the human immunodeficiency virus (also known as HIV, HIV), because of the lack of effective treatment drugs, the incidence of many HIV-related diseases was also quite high, and HIV-related dementia was one of them.

    Among those with advanced HIV infection at that time, the prevalence of HIV-related dementia was about 15%, and the annual incidence was 7% [1].

    However, with the advent of antiretroviral therapy (ART), more and more patients can get better virus suppression and immune recovery, and HIV-related diseases are less and less appearing in these patients.

    In the asymptomatic period, some HIV-infected people have already experienced mild cognitive impairment.

    Even if virological suppression is achieved, there are still patients with mild cognitive impairment.

    While prolonging life expectancy, it is also very important to improve the quality of life of patients.
    Therefore, in addition to virological suppression, issues including long-term immune recovery, patient self-reported quality of life, and neuropsychological health have gradually received attention in recent years.

    In the field of cognitive impairment, in the past few decades, many research directions have emerged, and many questions have been raised for discussion.
    For example, what criteria should be used to define the cognitive impairment of HIV-infected persons? What factors does it have to do with? How to screen, diagnose and manage this cognitive impairment? In this regard, we specially invited Professor Shi Chuan from Peking University Sixth Hospital to conduct a comprehensive review of discussions in this field.01 Controversy over criteria for determining HIV-related cognitive impairment The currently widely used definition standard is the HIV-related neurocognitive impairment (HAND) standard proposed in 2007, also known as the Frascati standard, but there are some controversies in the practical application of the HAND standard.
    For example, Under the HAND standard, the incidence of HIV-related cognitive impairment is as high as 50%, which is inconsistent with observations in clinical practice [2], and a considerable part of the HIV-negative control group is also classified as cognitive impairment.

    It can be seen that the HAND standard is slightly loose, resulting in the possibility of false positives.
    This test report will undoubtedly put more pressure on the psychological state of HIV patients.

    In order to make up for the limitations of the HAND standard, there are currently some other definition standards.
    According to these standards, the incidence of cognitive impairment is significantly lower, but they still need more clinical verification.

    Table 1: Comparison of criteria for determining HIV-related cognitive impairment.
    In this context, it is clear that it is difficult to diagnose and screen for HIV-related cognitive impairment in clinical practice.
    It lacks “tools” and has many interfering factors.
    Many diseases and lifestyles, such as depression, anxiety, substance abuse, and drug use, will have an impact on cognitive function, and it is difficult to determine whether a patient’s cognitive impairment is related to HIV.

    02 Potential causes of HIV-related cognitive impairment There are many hypotheses about the underlying causes of HIV-related cognitive impairment, including HIV itself and the inflammation and complications it causes; HIV RNA escape; lifestyle; aging; and the toxicity of ART.

    After infection, HIV may use infected monocytes and lymphocytes to cross the blood-brain barrier and enter the brain.
    On the one hand, they may directly invade immune cells such as microglia in the brain [3], on the other hand It can also indirectly cause a continuous immune response through proteins such as glycoprotein gp120, which affects neurons [4].

    Neuronal damage caused by these mechanisms may not be reversed by ART.

    Although starting ART as early as possible can control HIV in plasma to an undetectable level, some patients will experience a rare cerebrospinal fluid HIV RNA escape, that is, the level of HIV RNA in cerebrospinal fluid is detectable or higher than that in plasma.
    HIV RNA levels. This may be related to the drug resistance of ART, low CD4 cell count and insufficient drug concentration in the cerebrospinal fluid.
    Studies have found that a potent protease inhibitor (PI) is an important risk factor for the escape of HIV RNA in the cerebrospinal fluid [5].

    However, it should be noted that the ART program based on synergistic PI is usually a dressing alternative for patients infected with drug-resistant virus strains.
    Therefore, whether it is the drug or the HIV RNA escape caused by drug resistance still needs to be verified by research.
    .

    In addition to the effects of HIV itself, HIV-infected people have a higher proportion of smoking, alcohol and drug abuse.
    These unhealthy lifestyles may also affect cognitive function through the toxicity of the central nervous system.

    The picture is from pexel.
    com.
    In addition, aging is also a big problem.
    Cognitive function declines with age.
    Will HIV infection accelerate aging and accelerate the decline of cognitive function? Studies in the field of epigenetics have shown that before the start of ART, HIV-infected people have a significantly higher age of DNA methylation than negative people, and HIV infection time is one of the risk factors for accelerating epigenetic aging[6 ] However, a number of longitudinal studies have yielded inconsistent results, and further studies are needed to clarify the influence of age.

    Finally, regarding the toxicity of ART, although ART has led to a sharp decline in the incidence of HIV-related dementia, some drugs have been found to have central nervous system toxicity in clinical practice, such as efavirenz (EFV).

    EFV has a wide range of neuropsychiatric side effects.
    Studies have shown that after receiving EFV-based ART, the cognitive ability of patients is worse than that of other therapies [7], and it is improved after stopping the drug [8,9].

    Integrase inhibitor drugs have also reported some neuropsychiatric side effects, such as Lategravir (RAL) and Dotegravir (DTG).

    Especially for DTG, in early clinical trials, some test results showed that the incidence of neuropsychiatric-related adverse events of DTG-based treatment programs was slightly higher than that of the control group, and some subsequent real-world studies showed more High rate of discontinuation caused by such adverse events.

    03 Management of HIV-related cognitive impairment Although the toxicity of ART may be one of the causes of HIV-related cognitive impairment, ART is still the main method for managing this type of cognitive impairment.
    Therefore, patients need to be less toxic and penetrate the blood-brain barrier More capable ART drugs.

    The results of a small clinical trial [10] showed that the regimen of dotegravir/abacavir/lamivudine (DTG/ABC/3TC) was converted to averevir/cobisstat/emtricitabine 4 weeks after /propofol tenofovir (EVG/c/FTC/TAF), the scores of the Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression (HAD) Scale were improved, and moderate to severe levels were reported at 24 weeks The proportion of neuropsychiatric adverse events, including insomnia, nervousness, and depression, also dropped significantly compared to baseline.

    The analysis results confirm that these improvements are related to switching treatment options.

    In terms of overall neurocognitive ability, the researchers also observed significant improvements.

    In addition to EVG/c/FTC/TAF, another drug based on FTC/TAF, Biktigravir (BIC)/FTC/TAF, may also be a potential choice.

    Although in two phase III clinical trials [11,12], the incidence of neuropsychiatric-related adverse events was similar to that of DTG-based therapies, the 48-week Patient Reported Outcome (PRO) study [13] showed that The incidence of fatigue, dizziness, nausea, and sleep disturbances in patients receiving the BIC/FTC/TAF regimen was lower than that of the DTG/ABC/3TC regimen.

    The picture is from pexel.
    com and the ART drugs with stronger ability to penetrate the blood-brain barrier mainly target the cerebrospinal fluid HIV RNA library, which can be characterized by the Central Nervous System Penetration Effectiveness (CPE) score.
    A single drug is based on the difference in penetration ability, CPE The score is between 1-4, the higher the score, the stronger the penetration ability.

    Studies have shown that for patients with HIV replication in plasma or cerebrospinal fluid, a high CPE score is associated with better cognitive improvement and a lower incidence of HAND [14,15].

    A clinical trial called Neuro+3 [16] found that: after the treatment plan of HAND patients was converted to a drug combination with a CPE score of 3 or more, and a total score of 9 or more, the overall defect score ( GDS) improved, the number of patients with HIV-related dementia under the HAND standard was reduced from 2 to 1, and the number of patients with mild cognitive impairment was reduced from 22 to 8.

    Multivariate analysis showed that the improvement of GDS score after changing the treatment plan was related to the total CPE score of the plan ≥ 9.

    Despite these trials, in general, there is a lack of high-level evidence research on the management of HIV-related cognitive impairment through interventions, and other adjuvant treatments, including calcium channel inhibitors, antioxidants, and tumor necrosis Factor-α inhibitors, acetylcholinesterase inhibitors and other tests have not achieved good results.

    Therefore, it is uncertain whether this kind of strategy of switching to ART can really improve cognitive impairment in a large-scale patient population.

    In addition to such strategies, researchers are also exploring other strategies, such as new drugs with stronger ability to penetrate the blood-brain barrier or changing the way of administration, including nasal administration and nanoparticle delivery of drugs.

    The advantage of nasal administration is that it is simple, does not need to penetrate the blood-brain barrier, avoids the first pass effect of the liver and the degradation of the drug by the enzyme in the stomach, and because the nasal mucosa is rich in blood vessels, this method can also improve the bioavailability of the drug Degree, reduce the dosage of medication.

    However, there are some challenges in the way of nasal administration, such as the low permeability of the nasal mucosa of high molecular weight drugs, the degradation of the drugs in the nasal cavity, and the feasibility of low-dose/volume administration.

     There have been many studies on nanotechnology in drug delivery, especially cancer drugs.
    This approach is more targeted, and can also reduce the dose and frequency of drug administration, and reduce the off-target toxicity of drugs.

    However, as a relatively new technology, the safety of nanoparticles in the human body after "unloading" drugs has always been controversial.
    Studies have suggested that they may interfere with normal physiological mechanisms [17].

    It can be seen from these discussions that at present, there are still no small challenges in defining, understanding and managing the cognitive dysfunction of HIV-infected persons.

    We may need to form a consensus judgment standard to understand the degree of influence of different risk factors on cognitive impairment and whether cognitive impairment can be prevented through interventions, and how to comprehensively manage patients, that is, take medicine, mental health, and life Multi-dimensional methods, including methods and social support, require more exploration to further reduce the occurrence and progression of HIV-related cognitive impairment and the adverse impact on the quality of life of patients.

    I believe that the problems raised in the above discussion must have been encountered more or less in clinical practice.

    The neuropsychological health of HIV-infected persons is inextricably linked with HIV infection itself and ART.
    So how should the diagnosis and treatment be done in the long-term disease management? In the China AIDS webinar on March 25, we will continue to discuss these issues.
    If you are interested, please continue to pay attention to Jizhi Doctor.
    Don't miss this rare opportunity. Scan the QR code to watch the live broadcast of the conference.
    Review of the China AIDS Webinar · Collecting Patient Report Outcomes (PRO) References[1] McArthur JC, Hoover DR, Bacellar H, et al.
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    [8] Hakkers CS, Arends JE, van den Berk GE, et al.
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    [10] Perez Valero I, Cabello A, Ryan P, et al.
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    Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489 ): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial[J].
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    [12] Sax PE, Pozniak A, Montes ML, et al.
    Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial[J].
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    [13] Wohl D, Clarke A, Maggiolo F, et al.
    Patient- reported symptoms over 48 weeks among participants in randomized, double-blind, phase III non-inferiority trials of adults with HIV on co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus co-formulated abacavir, dolutegravir, and lamivudine[J].
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    Expert profileProfessor Ishikawa Director of the Clinical Psychological Evaluation Center of Peking University Sixth Hospital Deputy Leader of the Schizophrenia Collaboration Group of the Chinese Medical Association Leader of the Psychological Task Force of the National Health Commission's Disease Control Bureau in Wuhan Member of the Eighth Committee Member of the Psychological Evaluation Committee of the Chinese Society of Psychosomatic Medicine Member of the Psychiatric Rehabilitation Work Committee of the Psychiatric Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Psychiatric Branch of the Beijing Medical Association, Secretary-General "Chinese Journal of Psychiatry", "Chinese Mental Health Journal" and "Chinese Fertility Editorial Board Member of Journal of Health, Journal of Affective Disorder, Schizophrenia Research review experts presided over and undertook 13 national, provincial and ministerial scientific and technological research and international cooperation projects, published 72 academic papers, SCI included 49 papers, editor-in-chief translation 3 Department, participated in the compilation and translation of 7 works. Get more latest literature, guidelines and cutting-edge information in the fields of infectious diseases, hepatitis, AIDS, etc.
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