ABSTRACT
PURPOSE OF REVIEW: Reducing the risk of HIV-associated neurocognitive disorders (HAND) is an elusive treatment goal for people living with HIV. Combination antiretroviral therapy (cART) has reduced the prevalence of HIV-associated dementia, but milder, disabling HAND is an unmet challenge. As newer cART regimens that more consistently suppress central nervous system (CNS) HIV replication are developed, the testing of adjunctive neuroprotective therapies must accelerate. RECENT FINDINGS: Successes in modifying cART regimens for CNS efficacy (penetrance, chemokine receptor targeting) and delivery (nanoformulations) in pilot studies suggest that improving cART neuroprotection and reducing HAND risk is achievable. Additionally, drugs currently used in neuroinflammatory, neuropsychiatric, and metabolic disorders show promise as adjuncts to cART, likely by broadly targeting neuroinflammation, oxidative stress, aerobic metabolism, and/or neurotransmitter metabolism. Adjunctive cognitive brain therapy and aerobic exercise may provide additional efficacy. Adjunctive neuroprotective therapies, including available FDA-approved drugs, cognitive therapy, and aerobic exercise combined with improved cART offer plausible strategies for optimizing the prevention and treatment of HAND.
Subject(s)
AIDS Dementia Complex , HIV Infections , AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/prevention & control , HIV Infections/complications , HIV Infections/drug therapy , Humans , Neurocognitive Disorders/etiology , Neurocognitive Disorders/prevention & control , Neuroprotection , Neurotransmitter Agents/therapeutic use , Receptors, Chemokine/therapeutic useABSTRACT
OBJECTIVES: To investigate the associations of plasma lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and tenofovir (TFV) concentrations with cognitive function in a cohort of treated people with HIV (PWH). METHODS: Pharmacokinetics (PK) and cognitive function (Cogstate, six domains) data were obtained from PWH recruited in the POPPY study on either 3TC/ABC or FTC/tenofovir disoproxil fumarate (TDF)-containing regimens. Association between PK parameters (AUC0-24: area under the concentration-time curve over 24 hours, Cmax: maximum concentration and Ctrough: trough concentration) and cognitive scores (standardized into z-scores) were evaluated using rank regression adjusting for potential confounders. RESULTS: Median (IQR) global cognitive z-scores in the 83 PWH on 3TC/ABC and 471 PWH on FTC/TDF were 0.14 (-0.27, 0.38) and 0.09 (-0.28, 0.42), respectively. Higher 3TC AUC0-24 and Ctrough were associated with better global z-scores [rho = 0.29 (p = 0.02) and 0.27 (p = 0.04), respectively], whereas higher 3TC Cmax was associated with poorer z-scores [rho = -0.31 (p<0.01)], independently of ABC concentrations. Associations of ABC PK parameters with global and domain z-scores were non-significant after adjustment for confounders and 3TC concentrations (all p's>0.05). None of the FTC and TFV PK parameters were associated with global or domain cognitive scores. CONCLUSIONS: Whilst we found no evidence of either detrimental or beneficial effects of ABC, FTC and TFV plasma exposure on cognitive function of PWH, higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance.
Subject(s)
Anti-HIV Agents/blood , Cognition/drug effects , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/blood , AIDS Dementia Complex/blood , AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/prevention & control , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cross-Sectional Studies , Drug Therapy, Combination , Female , HIV Infections/blood , HIV Infections/psychology , Humans , Male , Mental Status and Dementia Tests , Middle Aged , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/therapeutic use , Socioeconomic Factors , Viral LoadABSTRACT
Approximately 15-40% of people living with HIV develop HIV-associated neurocognitive disorders, HAND, despite successful antiretroviral therapy. There are no therapies to treat these disorders. HIV enters the CNS early after infection, in part by transmigration of infected monocytes. Currently, there is a major opioid epidemic in the United States. Opioid use disorder in the context of HIV infection is important because studies show that opioids exacerbate HIV-mediated neuroinflammation that may contribute to more severe cognitive deficits. Buprenorphine is an opioid derivate commonly prescribed for opiate agonist treatment. We used the EcoHIV mouse model to study the effects of buprenorphine on cognitive impairment and to correlate these with monocyte migration into the CNS. We show that buprenorphine treatment prior to mouse EcoHIV infection prevents the development of cognitive impairment, in part, by decreased accumulation of monocytes in the brain. We propose that buprenorphine has a novel therapeutic benefit of limiting the development of neurocognitive impairment in HIV-infected opioid abusers as well as in nonabusers, in addition to decreasing the use of harmful opioids. Buprenorphine may also be used in combination with HIV prevention strategies such as pre-exposure prophylaxis because of its safety profile.
Subject(s)
AIDS Dementia Complex/prevention & control , Buprenorphine/therapeutic use , HIV Infections/drug therapy , AIDS Dementia Complex/complications , AIDS Dementia Complex/virology , Animals , Antigens, Ly/metabolism , Brain/pathology , Buprenorphine/pharmacology , Chronic Disease , Cognitive Dysfunction/complications , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/virology , Disease Models, Animal , Inflammation/pathology , Male , Mice, Inbred C57BL , Monocytes/drug effects , Phenotype , Viral Load/drug effectsABSTRACT
OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.
Subject(s)
Anti-HIV Agents/cerebrospinal fluid , Anti-HIV Agents/pharmacokinetics , HIV Infections/drug therapy , Lamivudine/cerebrospinal fluid , Lamivudine/pharmacokinetics , Zidovudine/cerebrospinal fluid , Zidovudine/pharmacokinetics , AIDS Dementia Complex/prevention & control , Adult , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Drug Therapy, Combination , HIV Infections/metabolism , HIV-1/genetics , Humans , Lamivudine/blood , Lamivudine/therapeutic use , Male , RNA, Viral/blood , RNA, Viral/cerebrospinal fluid , Spinal Puncture , Stavudine/administration & dosage , Stavudine/blood , Stavudine/cerebrospinal fluid , Stavudine/therapeutic use , Viral Load , Zidovudine/blood , Zidovudine/therapeutic useABSTRACT
HIV infection of the CNS causes neuroinflammation and damage that contributes to the development of HIV-associated neurocognitive disorders (HAND) in greater than 50% of HIV-infected individuals, despite antiretroviral therapy (ART). Opioid abuse is a major risk factor for HIV infection. It has been shown that opioids can contribute to increased HIV CNS pathogenesis, in part, by modulating the function of immune cells. HIV enters the CNS within two weeks after peripheral infection by transmigration of infected monocytes across the blood brain barrier (BBB). CD14+ CD16+ monocytes are a mature subpopulation that is increased in number in the peripheral blood of HIV-infected people. Mature monocytes can be productively infected with HIV, and they transmigrate preferentially across the BBB in response to CCL2, a chemokine elevated in the CNS and CSF of HIV-infected people even with ART. Buprenorphine, an opioid derivate, is an opioid replacement therapy for heroin addiction. It is a partial agonist of µ-opioid receptor and full antagonist of κ-opioid receptor. The effects of buprenorphine on CCL2-mediated CD14+ CD16+ monocytes transmigration across the BBB, a critical mechanism that promotes neuroinflammation and HAND, have not been characterized. We showed for the first time that buprenorphine decreases several steps of CCL2-mediated human mature monocyte transmigration. We propose that buprenorphine treatment in the context of HIV infection could serve a dual purpose, to treat opioid addiction and also to reduce neuroinflammation. Additionally, buprenorphine may be used as a treatment for HAND not only in the context of opioid abuse.
Subject(s)
Buprenorphine/pharmacology , Chemokine CCL2/physiology , Monocytes/drug effects , Receptors, Opioid, mu/agonists , Transendothelial and Transepithelial Migration/drug effects , AIDS Dementia Complex/immunology , AIDS Dementia Complex/prevention & control , Buprenorphine/therapeutic use , Cell Adhesion/drug effects , Cells, Cultured , Chemotaxis, Leukocyte/drug effects , GPI-Linked Proteins/analysis , Humans , Inflammation/drug therapy , Intercellular Adhesion Molecule-1/metabolism , Lipopolysaccharide Receptors/analysis , Monocytes/cytology , Nuclear Pore Complex Proteins/metabolism , Opioid-Related Disorders/drug therapy , Receptors, IgG/analysis , Receptors, Opioid, kappa/antagonists & inhibitors , THP-1 Cells , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
BACKGROUND: Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits. METHODS: Therapy-naive, cognitively asymptomatic, HIV-positive individuals were randomly allocated on a 1â:â1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed. RESULTS: Of 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4 cell count 428 (209) and 414 (229) cells/µl, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, Pâ=â0.96 for differences between study arms]. A greater increase in frontal grey matter N-acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change -0.097 (SD 0.18), Pâ=â0.009], although this was not associated with changes in cognitive function (Pâ=â0.17). CONCLUSION: Maraviroc-intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment.
Subject(s)
AIDS Dementia Complex/prevention & control , Anti-HIV Agents/administration & dosage , Anti-Retroviral Agents/administration & dosage , HIV Infections/drug therapy , Maraviroc/administration & dosage , AIDS Dementia Complex/pathology , Adult , Antiretroviral Therapy, Highly Active/methods , Brain Chemistry , Female , HIV Infections/complications , Humans , Magnetic Resonance Imaging , Male , Treatment OutcomeABSTRACT
OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/µl. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350âcells/µl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS: The 592 participants had a median age of 34 years; median baseline CD4 count was 629âcells/µl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, Pâ=â0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (Pâ<â0.001 for increase from baseline). CONCLUSION: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500âcells/µl.
Subject(s)
AIDS Dementia Complex/prevention & control , Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , Secondary Prevention , AIDS Dementia Complex/pathology , Adult , CD4 Lymphocyte Count , Female , Humans , Longitudinal Studies , Male , Treatment OutcomeABSTRACT
High levels of cardiovascular fitness and physical activity are associated with higher levels of cognitive function in people with HIV, thus, they may reduce the risk of developing HIV-associated neurocognitive disorder (HAND). This study aimed to investigate the effects of a 16-week aerobic exercise intervention on cognitive function in people with HIV. Eleven participants living with HIV were recruited into the study. Participants were randomised into either an exercise group (n = 5), that completed a 16-week aerobic exercise programme training, 3 times per week (2 supervised sessions and one unsupervised session) or a control group (n = 6) that received no intervention. Outcomes measured included cognitive function (Montreal cognitive assessment (MOCA) and the Trail making tests A and B), aerobic fitness (modified Bruce protocol), sleep quality (Pittsburgh sleep quality index; PSQI) and physical activity levels (seven-day accelerometry). At baseline, higher levels of moderate physical activity were positively correlated with higher MOCA scores and levels of aerobic fitness were negatively associated with Trail A scores (P = 0.04 and P = 0.001 respectively). However, exercise training did not induce any significant improvements in cognitive function or aerobic fitness. The overall mean adherence rate to the exercise programme was 60%. In conclusion, in the present study a 16-week aerobic exercise intervention did not affect the cognitive function of participants with HIV. It is likely that longer intervention periods and/or higher adherence rates to exercise might be needed for an aerobic exercise programme to be effective in improving cognitive function in a cohort with no baseline cognitive impairments.
Subject(s)
Cognition Disorders/rehabilitation , Cognition/physiology , Exercise Therapy , Exercise/physiology , HIV Infections/rehabilitation , AIDS Dementia Complex/physiopathology , AIDS Dementia Complex/prevention & control , Accelerometry , Adult , Cognition Disorders/physiopathology , Cohort Studies , Female , HIV Infections/physiopathology , Humans , Male , Physical Fitness/physiologyABSTRACT
HIV-1 infection of the brain causes the neurodegenerative syndrome HIV-associated neurocognitive disorders (HAND), for which there is no specific treatment. Herein, we investigated the actions of insulin using ex vivo and in vivo models of HAND. Increased neuroinflammatory gene expression was observed in brains from patients with HIV/AIDS. The insulin receptor was detected on both neurons and glia, but its expression was unaffected by HIV-1 infection. Insulin treatment of HIV-infected primary human microglia suppressed supernatant HIV-1 p24 levels, reduced CXCL10 and IL-6 transcript levels, and induced peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Insulin treatment of primary human neurons prevented HIV-1 Vpr-mediated cell process retraction and death. In feline immunodeficiency virus (FIV) infected cats, daily intranasal insulin treatment (20.0 IU/200 µl for 6 weeks) reduced CXCL10, IL-6, and FIV RNA detection in brain, although PPAR-γ in glia was increased compared with PBS-treated FIV+ control animals. These molecular changes were accompanied by diminished glial activation in cerebral cortex and white matter of insulin-treated FIV+ animals, with associated preservation of cortical neurons. Neuronal counts in parietal cortex, striatum, and hippocampus were higher in the FIV+/insulin-treated group compared with the FIV+/PBS-treated group. Moreover, intranasal insulin treatment improved neurobehavioral performance, including both memory and motor functions, in FIV+ animals. Therefore, insulin exerted ex vivo and in vivo antiviral, anti-inflammatory, and neuroprotective effects in models of HAND, representing a new therapeutic option for patients with inflammatory or infectious neurodegenerative disorders including HAND. SIGNIFICANCE STATEMENT: HIV-associated neurocognitive disorders (HAND) represent a spectrum disorder of neurocognitive dysfunctions resulting from HIV-1 infection. Although the exact mechanisms causing HAND are unknown, productive HIV-1 infection in the brain with associated neuroinflammation is a potential pathogenic mechanism resulting in neuronal damage and death. We report that, in HIV-infected microglia cultures, insulin treatment led to reduced viral replication and inflammatory gene expression. In addition, intranasal insulin treatment of experimentally feline immunodeficiency virus-infected animals resulted in improved motor and memory performances. We show that insulin restored expression of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which is suppressed by HIV-1 replication. Our findings indicate a unique function for insulin in improving neurological outcomes in lentiviral infections, implicating insulin as a therapeutic intervention for HAND.
Subject(s)
AIDS Dementia Complex/prevention & control , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Neuritis/prevention & control , Neurodegenerative Diseases/prevention & control , Neurons/pathology , Neuroprotective Agents/therapeutic use , Administration, Intranasal , Animals , Cats , Cell Death/drug effects , Female , HIV-1 , Human Immunodeficiency Virus Proteins/metabolism , Humans , Hypoglycemic Agents/administration & dosage , Immunodeficiency Virus, Feline , Insulin/administration & dosage , Lentivirus Infections/metabolism , Neuroglia/drug effects , Neuroglia/metabolism , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/administration & dosage , Pregnancy , Receptor, Insulin/drug effectsABSTRACT
BACKGROUND: Over the past three decades, the clinical presentation of HIV infection of the Central Nervous System (CNS) has evolved. Prior to wide spread use of effective antiretroviral therapy (ART), more than a third of infected individuals exhibited a range of neurocognitive and motor deficits that frequently progressed to severe dementia and paralysis. However, the use of ART has significantly decreased the prevalence of severe forms of HIV-1 associated neurocognitive disorders (HAND). Studies of neurocognitive dysfunction have reported variable prevalence, ranging from 21% to 77.6%, defined primarily by mild to moderate neurocognitive impairment. HIV-associated chronic inflammation and associated neurotoxicity of long term ART, as well as the aging of the HIV-infected population, likely influence the pathogenesis of HAND. Despite significant research efforts directed towards a better understanding of the mechanisms underlying HIV neuropathogenesis, definitive causal pathophysiology of HAND and thus effective prevention or treatment remain elusive. Furthermore, HIV therapeutic research now includes efforts to effect a cure, by eliminating or silencing HIV within infected cells, which must include efforts to target the latently infected cells within the CNS. CONCLUSION: Prevention and treatment of the neurological complications of HIV, and eradication of persistent virus from the CNS compartment are major priorities for the HIV-CNS research. Here we give an overview of the progress of research on HIV-CNS disease, define new challenges and research areas, and highlight domestic and global priorities.
Subject(s)
AIDS Dementia Complex/prevention & control , AIDS Dementia Complex/physiopathology , HIV Infections/complications , HIV-1/pathogenicity , Host-Pathogen Interactions , Biomedical Research/trends , HumansABSTRACT
With the advent of highly effective antiretroviral therapy, cardiovascular disease has become an important cause of morbidity and mortality among people with treated HIV-1, but the pathogenesis is unclear. Platelet-activating factor is a potent lipid mediator of inflammation that has immunomodulatory effects and a pivotal role in the pathogenesis of inflammatory disorders and cardiovascular disease. Limited scientific evidence suggests that the platelet-activating factor pathway may be a mechanistic link between HIV-1 infection, systemic inflammation, and immune activation that contribute to pathogenesis of chronic HIV-related comorbidities, including cardiovascular disease and HIV-associated neurocognitive disorders. In this review, we examine the mechanisms by which the cross-talk between HIV-1, immune dysregulation, inflammation, and perturbations in the platelet-activating factor pathway may directly affect HIV-1 immunopathogenesis. Understanding the role of platelet-activating factor in HIV-1 infection may pave the way for further studies to explore therapeutic interventions, such as diet, that can modify platelet-activating factor activity and use of platelet-activating factor inhibitors that might improve the prognosis of HIV-1 infected patients.
Subject(s)
AIDS Dementia Complex/prevention & control , Antiretroviral Therapy, Highly Active , Cardiovascular Diseases/prevention & control , HIV Infections/therapy , Inflammation/therapy , Platelet Activating Factor/therapeutic use , AIDS Dementia Complex/immunology , AIDS Dementia Complex/physiopathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/physiopathology , Combined Modality Therapy , Comorbidity , Disease Progression , Feeding Behavior , HIV Infections/immunology , HIV Infections/physiopathology , Humans , Inflammation/immunology , Inflammation/physiopathology , Molecular Targeted TherapyABSTRACT
BACKGROUND: Despite the efficacy of highly active antiretroviral treatment (HAART), a large proportion of human immunodeficiency virus (HIV)-infected patients may develop moderate neurocognitive impairment. Antiretroviral drug passage into the central nervous system may be relevant for preventing and treating HIV-associated neurocognitive disorder; nevertheless, clear cerebrospinal fluid (CSF) pharmacodynamic targets are not known. METHODS: HAART-treated adults with wild-type HIV were prospectively enrolled. CSF concentrations (measured by mass spectrophotometric methods) and inhibitory quotients (CSF concentrations divided by in vitro 50% and 95% inhibitory concentrations) were compared among different drugs and related to CSF HIV RNA levels. CSF escape was defined as CSF HIV RNA >50 copies/mL despite contemporary plasma HIV RNA below that threshold. RESULTS: One hundred twenty-seven patients (91 male [71.7%], 93 white [73.2%], with a median age of 46 years [interquartile range, 40.5-54.5 years]) provided 174 paired CSF and plasma samples. Twice-daily darunavir, once-daily darunavir, and efavirenz had the highest CSF 95% inhibitory quotients (18.5, 8.2, and 6.4, respectively). Higher nadir CD4 cell count (P = .01) and plasma HIV RNA <50 copies/mL (P < .001) were independent predictors of controlled CSF HIV RNA. Optimal drug exposure (CSF detectable drugs and 95% inhibitory quotient >1) was protective for CSF escape (P = .01). CONCLUSIONS: Cerebrospinal fluid 95% inhibitory quotients may be used to compare antiretroviral drug compartmental exposure; they deserve longitudinal studies to assess the adequacy of CSF drug concentrations in treated HIV-infected patients.
Subject(s)
AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/prevention & control , Anti-Retroviral Agents/pharmacokinetics , Cerebrospinal Fluid/chemistry , HIV Infections/complications , HIV Infections/drug therapy , HIV/isolation & purification , AIDS Dementia Complex/virology , Adult , Anti-Retroviral Agents/therapeutic use , Cerebrospinal Fluid/virology , Female , HIV Infections/virology , Humans , Inhibitory Concentration 50 , Male , Mass Spectrometry , Middle Aged , Prospective Studies , Treatment OutcomeABSTRACT
OBJECTIVE: To assess changes over time in neuropsychological test results (NPr) and risk factors among a regularly followed HIV-infected patient population. METHODS: Prospective cohort of HIV-infected patients randomly selected to undergo neuropsychological follow-up. Test score was adjusted for age, sex and education. Patients were divided into five groups: normal tests, neuropsychological deficit (one impaired cognitive domain), asymptomatic neurocognitive disorders (ANIs), mild neurocognitive disorders (MNDs) and HIV-associated dementia (HAD). Demographic and background parameters including CSF drug concentration penetration effectiveness (CPE) score 2010 were recorded. Changes in NPr and associated risk factors were analyzed. RESULTS: Two hundred and fifty-six patients underwent neuropsychological tests and 96 accepted follow-up approximately 2 years later. The groups were comparable. Upon neuropsychological retesting, six patients improved, 31 worsened and 59 were stable. The proportion of patients with HIV-associated neurocognitive disorders (HANDs) rose from 26 to 45%, with ANIs and MNDs still mostly represented. Most patients initially diagnosed with HANDs remained stable, five of 25 showed clinical improvement and three of 25 deteriorated. Of 33 patients with normal tests, four deteriorated, whereas 24 of 38 with initial neuropsychological deficit had poorer NPr, and contributed most of the new HAND cases. Patients with clinical deterioration had a lower CPE score both at inclusion (6.9 vs. 8.1; P = 0.005) and at the end of follow-up (7.2 vs. 7.8; P = 0.08) than those with improved or stable performance. This was confirmed by multivariate analysis. CONCLUSION: Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration.
Subject(s)
AIDS Dementia Complex/epidemiology , AIDS Dementia Complex/prevention & control , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/pharmacokinetics , HIV Infections/complications , HIV Infections/drug therapy , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Young AdultABSTRACT
Human immunodeficiency virus type-1 (HIV) causes mild or severe neurological problems, termed HIV-associated neurocognitive disorder (HAND), even when HIV patients receive antiretroviral therapy. Thus, novel adjunctive therapies are necessary to reduce or abolish the neurotoxic effect of HIV. However, new therapies require a better understanding of the molecular and cellular mechanisms of HIV-induced neurotoxicity. HAND subjects are characterized by being profoundly depressed, and they experience deficits in memory, learning and movements. Experimental evidence has also shown that HIV reduces neurogenesis. These deficits resemble those occurring in premature brain aging or in a brain with impaired neural repair properties. Thus, it appears that HIV diminishes neuronal survival, along with reduced neuronal connections. These two phenomena should not occur in the adult and developing brain when synaptic plasticity is promoted by neurotrophic factors, polypeptides that are present in adult synapses. This review will outline experimental evidence as well as present emerging concepts for the use of neurotrophic factors and in particular brain-derived neurotrophic factor as an adjunct therapy to prevent HIV-mediated neuronal degeneration and restore the loss of synaptic connections.
Subject(s)
AIDS Dementia Complex/prevention & control , Brain/drug effects , Nerve Growth Factors/pharmacology , Neuronal Plasticity/drug effects , Animals , Brain-Derived Neurotrophic Factor/pharmacology , HumansABSTRACT
We evaluated factors associated with improvement in neurocognitive performance in 258 HIV-infected adults with baseline CD4 lymphocyte counts above 350 cells/mm³ randomized to intermittent, CD4-guided antiretroviral therapy (ART) (128 participants) versus continuous therapy (130) in the Neurology substudy of the Strategies for Management of Antiretroviral Therapy trial. Participants were enrolled in Australia, North America, Brazil, and Thailand, and neurocognitive performance was assessed by a five-test battery at baseline and month 6. The primary outcome was change in the quantitative neurocognitive performance z score (QNPZ-5), the average of the z scores of the five tests. Associations of the 6-month change in test scores with ART use, CD4 cell counts, HIV RNA levels, and other factors were determined using multiple regression models. At baseline, median age was 40 years, median CD4 cell count was 513 cells/mm³, 88 % had plasma HIV RNA ≤ 400 copies/mL, and mean QNPZ-5 was -0.68. Neurocognitive performance improved in both treatment groups by 6 months; QNPZ-5 scores increased by 0.20 and 0.13 in the intermittent and continuous ART groups, respectively (both P < 0.001 for increase and P = 0.26 for difference). ART was used on average for 3.6 and 5.9 out of the 6 months in the intermittent and continuous ART groups, respectively, but the increase in neurocognitive test scores could not be explained by ART use, changes in CD4, or plasma HIV RNA, which suggests a practice effect. The impact of a practice effect after 6 months emphasizes the need for a control group in HIV studies that measure intervention effects using neurocognitive tests similar to ours.
Subject(s)
AIDS Dementia Complex/prevention & control , Anti-Retroviral Agents/administration & dosage , HIV Infections/drug therapy , Learning , Neuropsychological Tests , Adult , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: In patients who remain virologically suppressed in plasma with triple-drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease inhibitor monotherapy is associated to a higher rate of neurocognitive impairment. METHODS: In this observational, cross-sectional study we included patients with plasma virological suppression (≥ 1 year) without concomitant major neurocognitive confounders, currently receiving for ≥ 1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed. RESULTS: Of the 191 included patients--triple therapy: 96, 1-2 years of monotherapy: 40 and >2 years of monotherapy: 55--proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9-33.6); triple therapy, 31.6% (22.1-41.0); short-term monotherapy, 25.0% (11.3-38.7); long-term monotherapy: 21.4% (10.5-32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29-2.50) and for long-term monotherapy 0.40 (0.14-1.15). CONCLUSIONS: Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART.
Subject(s)
AIDS Dementia Complex/prevention & control , Antiretroviral Therapy, Highly Active , HIV Protease Inhibitors/therapeutic use , HIV-1/drug effects , Lopinavir/therapeutic use , Ritonavir/therapeutic use , Sulfonamides/therapeutic use , AIDS Dementia Complex/psychology , AIDS Dementia Complex/virology , Adult , Cross-Sectional Studies , Darunavir , Drug Administration Schedule , Drug Resistance, Viral/drug effects , Female , HIV-1/physiology , Humans , Male , Middle Aged , Neuropsychological Tests , Viral Load/drug effectsABSTRACT
Human immunodeficiency virus (HIV)-associated neurological complications continue to occur despite the development in antiretroviral treatment. New forms of old opportunistic infections and increased prevalence of neurocognitive disorders are the challenges that infectious diseases specialists face in daily clinic. How to screen and treat these disorders are subject of debate and new studies are underway to answer these questions. This review focuses on a brief discussion about opportunistic infections still present in late diagnosed HIV-infected patients and describes new forms of HIV-related neurological complications.