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Neurocognitive Disorders Threaten HIV+
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Jules Levin
CROI 2009 Feb 8-12 Montreal
It is obvious that neurocognitive disorders are a major concern in HIV+ individuals, particularly as they age because neurlogic decline occurs in the general population of aging individuals so it appears that HIV+ individuals are at significant risk for worse decline as they age. I have discussed these issues many times: studies suggest that aging with HIV may increase risk for alzheimer's and parkinsns, but we haven't adequately studied this yet; at CROI several study report that cognitive impairment and neuropathy can persist despite HAART as people age. Although we are beginning to discuss these issues little or nothing has been done to discuss how to address these problems with intervention, and these problems will obviously be present globally in the future, perhaps worse in underdeveloped countries. Of course in addition to neurcognitive problems additional conditions are threatening those aging with HIV including bone loss and fractures, fractures increase mortality in the elderly in the general population and of course HIV+ individuals aging with HIV face increased risk for heart disease, diabetes and kidney disease. It is time for researchers to discuss potential solutions.
Here are several poster reports from CROI on neurocognitive disorders and function in HIV+ individuals. The first 2 posters report high prevalence (51% and 24%) of neurocognitive disorders despite using HAART. The 3rd study suggests cytokine dysfunction may persist in the brain despite HAART in patients with neurocognitive disorder. Another study reports CD4 nadir is associated with neurologic dysfunction despite HAART and this has been found in many studies CD4 nadir appears to predict neurologic dysfunction. A study from the CHARTER Study group found 41% of patients with undetectable HIV in the blood had HIV in the CSF when they used a sensitive assay (<2 copies/ml) and having these low levels was associated with cognitive impairment than patients with detectable HIV in both the blood and the CSF, the authors suggest this is because their HAART regimen was not effective enough in the CSF, didn't have enoiugh CSF penetration. The CHARTER group in an other study reported that substance abuse was not associated with cognitive impairment, the implication is that when HIV is found to be associated with neurocognitive disorders if the patient had a history of substance abuse it is the HIV at fault not the substance abuse.
High Prevalence (24%) of Mild Neurocognitive Disorders in HIV-infected Patients, ANRS CO3 Aquitaine Cohort: "For every 4 treated adults with well controlled HIV-infection, 1 had a mild cognitive disorder as compared to 6% in the French general population of 65 years or older"
Fabrice Bonnet*1,2,3, H Amieva1, M Bruyand1,2,3, F-A Dauchy2,3, P Morlat1,2,3, F Dabis1,2,3, P Mercie1,2,3, J-F Dartigues1, G Chene1,2,3, C Lewden1,3, and the ANRS CO3 Aquitaine Cohort
1INSERM U897, Bordeaux, France; 2CHU de Bordeaux, France; and 3Univ Victor Segalen Bordeaux 2, ISPED, France
Background: With the use of ART, the prevalence of HIV dementia has decreased. However, individuals chronically HIV infected experience mild neurocognitive disorders. We assessed the frequency and factors associated with mild neurocognitive disorders in a large cohort of HIV-infected patients.
Methods: In a cross-sectional study, a consecutive sample of HIV-infected adults from the ANRS CO3 Aquitaine Cohort has been evaluated with a neuropsychological battery assessing episodic and working memory, executive functions, language, and psychomotor speed. Mild neurocognitive disorder was defined according to the revised research criteria for HIV-associated cognitive disorders as a performance of ≥1 standard deviation below the normative mean in ≥2 neuropsychological tests. Determinants were studied through a multivariate logistic regression model. Moreover, the distribution of subjects' test scores was divided in quartiles (the lower quartile reflecting poorer performance) and Kruskall-Wallis test was performed to assess the statistical association between cognitive performances and CD4 nadir.
Results: We have so far enrolled 230 patients (180 men): median age, 46 years, median CD4 count 505/mm3, 88% treated with ART, and 80% had HIV RNA <500 copies/mL.
A mild neurocognitive disorder was diagnosed in 55 patients (24%; 95%CI 18 to 29%).
In multivariate analysis, older age (OR = 1.1 for 1 additional year; CI 1.0 to 1.1), professional inactivity or retired status (OR = 2.8 vs professional activity; CI 1.3 to 6.2), low educational level (OR = 13.6 vs graduate patients; CI 4.4 to 42.0), AIDS stage (OR = 2.4, CI 1..0 to 5.3), and positive hepatitis B surface antigen (HBsAg) (OR = 4.0, CI 1.1 to 14.2) were significantly associated with a higher prevalence of mild neurocognitive disorder. A lower nadir of CD4 was significantly associated with the lowest quartile of the scores' distribution for the following tests: free and cued selective reminding test (episodic memory), the trail-making test-B (executive functions), and the digit symbol substitution task (psycho-motor speed).
Conclusions: For every 4 treated adults with well controlled HIV-infection, 1 had a mild cognitive disorder as compared to 6% in the French general population of 65 years or older. In addition to factors usually associated with mild neurocognitive disorders in the aging general population, advanced HIV infection and co-infection with hepatitis B may explain the high frequency in HIV population. A short battery of easy-to-administer tests could be used to explore mild neurocognitive disorders in HIV-infected patients.
High Frequency (51%) of Neurocognitive Disorders in Older HIV-infected Patients despite a Sustained Virological and Immunological Response on cART: The Sigma Study
A Dulioust1, N Lerolle1, P Dolphin1, F Boufassa2, M Duracinsky1, J-F Delfraissy1, C Goujard1, and Jacques Gasnault*1
1Bicetre Hospital, APHP, Le Kremlin Bicetre, France and 2INSERM U822, Univ Paris Sud XI, Le Kremlin Bicetre
Background: During aging, HIV infection could accelerate the emergence of cognitive disorders, despite the widespread use of virologically effective combination ART (cART).
Methods: We report here the neurocognitive subset (Neurosigma) of the Sigma study, an observational, cross-sectional study designed to describe the medical conditions and the psychosocial status of patients aged 60 years and more in the Bicetre HIV Cohort, a hospital cohort of 1350 HIV-infected patients. Demographic data, medical and therapeutic history, cardiovascular risk (CVR), plasma HIV RNA levels, and CD4 counts since HIV diagnosis were collected. Subjects with active neurologic or psychiatric diseases and low educational level were excluded. Subjects underwent a brief neuropsychological exam using the Trailmaking A/B and the Digit Symbol yielding a composite NPZ3 score (assessing psychomotor speed, attention, cognitive sequencing, and shifting cognitive sets). The Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Instrumental Activity of Daily Living (IADL) were performed.
Results: Among the 66 patients older than 60 years, 37 (56%) achieved the Neurosigma substudy. At enrolment, all patients except 1 were treated with cART; 73% were men. Median age was 67 years (range 60 to 84). Median duration of HIV infection and of ART were respectively 11 (IQR 5 to 17) and 10 (IQR 3 to 14) years. Median nadir CD4 count was 113 cells/μL (IQR 80 to 239), whereas the last median CD4 count was 522 cells/μL (IQR 443 to 675). HIV RNA was <50 copies/mL in all treated patients.
One or more CVR factors was present in 27 patients (diabetes 27%, hypertension 49%, dyslipidemia 43%). A neurocognitive impairment was detected in 19 patients (51%). MMSE was abnormal (<-1.65 SD) in 6 (16%) patients. Severe impairment (<-2) of NPZ3 was observed in 11 patients (30%) including 4 with abnormal IADL and mild (-2≦NPZ3<-1) in 8 (21%). GDS was abnormal (>5) in 7 patients (19%).
Conclusions: Despite a sustained response to cART, neurocognitive disorders are more frequent in old HIV+ patients than in the general aging population, but are underdiagnosed by their physicians. In our patients, subcortical types of cognitive impairment remain more predominant than neocortical types. The respective role of HIV, ART, and co-morbidities is debated. Longitudinal studies are needed to assess the outcome of these disorders in aging and to determine their predictive factors.
"irrespective of HIV RNA control in CSF cytokine and chemokine CSF expression was not modified by ART. Both findings suggest a major role of pro-inflammatory cytokines in the pathogenetic mechanisms of HAND development in advanced HIV infected patients."
Intrathecal Immune Activation and Viral Changes in HIV-infected Naive Patients with Advanced Disease after Short-term HAART Introduction
Monica Airoldi*1, E Suardi1, A Soria1, N Squillace1, S Melzi1, M Gregorio2, D Trabattoni3, M Clerici3, A Gori1, and A Bandera1
1Division of Infectious Diseases, Department of Internal Medicine, "San Gerardo" Hospital, University Milano-Bicocca, Monza, Italy; 2Don Carlo Gnocchi Foundation, Milan, Italy; and 3Department of Preclinical Sciences, Chiar of Immunology, University of Milan, Milan, Italy
-- HIV enters the CNS during the initial phases of infection, replicating in different cellular populations in each phase of the disease and leading to compartmentalization of HIV infection.
-- HIV-associated neurocognitive disorders (HANDs) affects up to 30% of HIV-infected people, and up to 50% of HIV-positive advanced- naive patients despite the introduction of HAART.
-- Development of HANDs seems to be due to a double mechanism: viral replication in the CNS by itself and the subsequent intrathecal immune activation, principally sustained by activated glial cells and macrophages
Background: Compartmentalization of HIV in central nervous system (CNS) can lead to HIV-associated neurocognitive disorders (HAND), either for persistent HIV replication in CNS or for HIV-related CNS immune activation. We correlate the change of CNS viral parameters and immune activation in naive HIV-infected patients with advanced disease with or without HAND after ART introduction.
Methods: HIV-infected patients with CD4 <200/μL starting ART with zidovudine (ZDV)/lamivudine (3TC) and lopinavir/ritonavir (LPV/r). Neurocognitive tests were performed at baseline. HIV RNA, pro-inflammatory cytokines (interleukin [IL] -6, IL-10, interferon [INF] -ϒ, tumor necrosis factor [TNF] -α, tumor growth factor [TGF] -β1, TGF-β2) and chemokines (macrophage inhibitory protein [MIP] -1α, MIP-1β, MCP-1) were measured on plasma and cerebrospinal fluid (CSF) at baseline and T3 by enzyme-linked immunosorbent assay. Wilcoxon log rank sum test was used.
Results:
At baseline HAND was diagnosed in 5 of 10 patients. Baseline CSF HIV RNA levels were not different between patients with normal and impaired tests (3.26 log10 vs 3.36 log10 copies/mL). Conversely when cytokine and chemokine expression was compared between the 2 groups, 10-fold higher median CSF IL-6 (3.5 vs 0.3 pg/mL) and MIP-1β levels (2.1 vs 1.1 pg/mL) were found in patients with HAND as compared to patients with normal cognitive function. All patients receiving ART showed significant decrease in plasma and CSF HIV RNA levels. However all the patients displayed a significant discrepancy in the HIV RNA in plasma and CSF D levels between T0 and T3 (1.5 log10 copies/mL vs 0.0 log10 copies/mL, respectively), indicating a slower HIV decrease in CSF than in plasma.
Despite the significant drop in HIV RNA both in plasma and in CSF no significant change in cytokine and chemokine expression were observed in CSF from T0 to T3 either in patients with HAND or in patients without CNS involvement. In particular, despite effective ART, IL-6 and MIP-1β remained persistently higher in patients presenting HAND.
Conclusions: HIV RNA decrease at a different rate in plasma and in CSF, which supports the hypothesis of compartmentalization of HIV replication in advanced disease. CSF HIV RNA levels did not seem to be primarily associated with impaired neurocognitive function. Conversely, pro-inflammatory cytokines levels were strictly associated to the development of cognitive disorders. Moreover, irrespective of HIV RNA control in CSF cytokine and chemokine CSF expression was not modified by ART. Both findings suggest a major role of pro-inflammatory cytokines in the pathogenetic mechanisms of HAND development in advanced HIV infected patients.
Cortical and Subcortical Volumes on Magnetic Resonance Imaging Associated with HIV History and Current Disease Status: "HIV severity and duration related to reduced cortical and hippocampal volumes, suggesting that patients who suffered prior severe immune dysfunction (low CD4 nadir) may eventually experience cortical and hippocampal changes even in the context of HAART. This is noteworthy, as these brain areas were not viewed as primary sites of HIV infection in the past, suggesting an evolution of cortical disturbances with chronic HIV infection that requires further investigation."
R Cohen1, Jaroslaw Harezlak*2, D Tate3, C Yiannoutosos2, M Taylor4, G Schifitto5, C Guttmann3, G Hana1, U Clark1, B Navia6, and HIV Neuroimaging Consortium
1Warren Alpert Med Sch, Brown Univ, Providence, RI, US; 2Indiana Univ Sch of Med, Indianapolis, US; 3Harvard Med Sch, Boston, MA, US; 4Univ of California, San Diego Med Ctr, US; 5Univ of Rochester Sch of Med, NY, US; and 6Tufts Univ Sch of Med, Boston, MA, US
Background: Despite reduced prevalence of HIV-associated dementia in the HAART era, HIV continues to affect the brains of patients with chronic infection. The effects of duration of HIV infection in the aging brain relative to the severity of current and prior immune system dysfunction remains unresolved. We hypothesized that CD4 nadir, illness duration, and age would be associated with reduced cortical volumes.
Methods: Cross-sectional analyses were conducted on MPRAGE brain MRI from HIV+ patients (n = 82). Brain segmentation by voxel-based morphometry (SPM-5), with AAL to determine frontal, parietal, temporal, occipital, caudate, putamen, and hippocampal, and total gray and white matter, and ventricular volumes was performed. Current CD4, CD4 nadir, plasma viral load, ADC stage, time since HIV diagnosis, age, education, gender, and race were entered as independent measures into linear regression analyses with each brain ROI as a dependent variable. Final models were selected by minimizing Akaike Information Criterion (AIC), which balances model fit and complexity.
Results:
Smaller frontal (adj. R2 = 0.07) and temporal (adj. R2 = 0.15) volumes were associated with CD4 nadir less than 50 and greater duration of infection. Smaller parietal volume (adj. R2 = 0.15) was associated with longer time since diagnosis and ADC stage <1. Hippocampal volume (adj. R2 = 0.08) was associated with all 3 of these variables. Caudate volume (adj. R2 = 0.08) was associated with detectable current plasma viral load and ADC stage >1. The putamen was not significantly associated with any HIV variable. Total white matter volume (adj. R2 = 0.08) was associated with CD4 nadir, while ventricular volume (adj. R2 = 0.09) was associated with ADC stage and longer HIV duration. Age did not contribute significantly to any of these associations.
Conclusions: Caudate volume was associated with current plasma viral load, as expected based on evidence from the pre-HAART. In contrast, HIV severity and duration related to reduced cortical and hippocampal volumes, suggesting that patients who suffered prior severe immune dysfunction may eventually experience cortical and hippocampal changes even in the context of HAART. This is noteworthy, as these brain areas were not viewed as primary sites of HIV infection in the past, suggesting an evolution of cortical disturbances with chronic HIV infection that requires further investigation.
Low-Level HIV in CSF When HIV-RNA is < 50 Tied to Type of ART and Worse Cognitive Function - written by Mark Mascolini - (02/13/09)
Persistent HIV in the Central Nervous System during Treatment is Associated with Worse ART Penetration and Cognitive Impairment: "ART-treated individuals frequently (41%) have low levels of HIV in CSF which is associated with less penetrant ART. At least a quarter of these individuals appear to have HIV that persists solely within the central nervous system (detectable HIV in CSF but not in blood) and these individuals have much worse cognitive performance than those who appear to have a systemic source of HIV. We conclude that people living with HIV may have cognitive impairment as a result of ART that is incompletely effective in the nervous system. A more sensitive HIV assay may be needed to monitor CSF in treated individuals."
Scott Letendre*1, D McClernon2, R Ellis1, J Munoz-Moreno3, L Way1, D Franklin1, R Heaton1, I Grant1, and the CHARTER Group
1Univ of California, San Diego, US; 2McClernon LLC, Cary, NY, US; and 3Hosp Univ Germans Trias i Pujol, Barcelona, Spain
Background: Cognitive impairment can occur or persist during ART. Explanations include co-morbidities, neurotoxic ART, persistent neuroinflammation, or persistent HIV replication. This analysis assessed whether low levels of HIV in CSF were associated with inter-individual differences in ART and neuropsychological (NP) performance.
Methods: We selected 300 participants from the CHARTER cohort because they were taking ART, had HIV RNA levels <50 copies/mL (Roche Amplicor) in cerebrospinal fluid (CSF) and blood, and had at least 2 mL of specimen in storage at -70 C. CSF specimens were assayed with a modified version of the NucliSens EasyQ (bioMerieux) assay capable of qualitatively detecting HIV at 2 copies/mL. Those who had detectable HIV in CSF were identified and 100 matched plasma specimens (obtained within 1 hour of CSF) were also assayed. Penetration of ART into the CNS was estimated by CNS Penetration-Effectiveness (CPE) ranks. Global NP performance was summarized by a validated method. Analyzes were performed using univariate (Fisher's exact test, t test) and multivariate (logistic regression) methods.
Results:
Participants were mostly non-white (54%), middle-aged (mean 45 years), men (76%) with AIDS (74%) who were HCV seronegative (74%).. Median duration of ART was 16 months. Median CD4 count was 535/μL; 122 (41%) had detectable HIV in CSF.
Detectable HIV was associated with worse CPE scores (mean 1.5 vs 1.7, d = 0.25, p = 0.03) and HCV seronegativity (81% vs 69%, p = 0.03).
Multivariate analysis confirmed that HIV in CSF was associated with both worse CPE scores and HCV seronegativity. Among the 100 matched plasma specimens selected for assay, 26% had undetectable HIV (i.e., undetectable in plasma with detectable HIV in CSF). These individuals had worse NP performance (mean Global Rating 5.3 vs 4.1, d = 0.71, p = 0.006, see the figure) than those who had detectable HIV in both fluids.
Conclusions: ART-treated individuals frequently (41%) have low levels of HIV in CSF which is associated with less penetrant ART. At least a quarter of these individuals appear to have HIV that persists solely within the central nervous system (detectable HIV in CSF but not in blood) and these individuals have much worse cognitive performance than those who appear to have a systemic source of HIV. We conclude that people living with HIV may have cognitive impairment as a result of ART that is incompletely effective in the nervous system. A more sensitive HIV assay may be needed to monitor CSF in treated individuals.
Reduced Region-specific Corpus Callosum Volumes Correlate with Low-nadir CD4 and Decreased Cognition in HIV-infected Carriers of the ApoE4 Allele
Kalpana Kallianpur*1, A McMurtray1, V Valcour1,2, B Shiramizu1, and C Shikuma1
1Hawaii AIDS Clinical Res Prgm, Univ of Hawaii, Honolulu, US and 2Univ of California, San Francisco, US
Background: Low nadir CD4 cell count and the apolipoprotein E4 (ApoE4) allele are known risk factors for HIV-related neurocognitive impairment. ApoE4 is also predictive of development or progression of Alzheimer's disease. The severity of dementia in HIV infection has been correlated to diffusion alterations within the corpus callosum, and in Alzheimer's disease, with regionally specific atrophy of the same structure. We hypothesize that volumetric changes in callosal regions may correlate with nadir CD4, presence of an ApoE4 allele, and neurocognitive deficits.
Methods: A total of 17 HIV-seropositive men over age 50 (8 with at least 1 ApoE4 allele; 9 without ApoE4) prospectively underwent T1-weighted structural magnetic resonance imaging at 3.0 Tesla, clinical and neuropsychological tests, and ApoE4 genotyping. Nadir CD4 count was determined by patient self-report and confirmed as possible. We utilized FreeSurfer software to parcellate corpus callosum into five segments. Analysis of co-variance was used to study the effects of callosal volumes on cognitive domains in which neuropsychological test performance differed significantly (p <0.05) between ApoE4+ and non-ApoE4 groups. Independent variables were age, education, ApoE4 group status, and callosal segment volume. Regional volumes that were associated with cognitive deficit were examined for correlation with nadir CD4.
Results:
Education, viral load and current CD4 count did not differ significantly between ApoE4+ and non-ApoE4 groups. Reductions of normalized total and regional callosal volume in ApoE4 carriers did not reach significance. Significant ApoE4-associated impairment included diminished visuospatial function and non-verbal memory, which showed effects at significant or trend (p <0.1) levels of splenium (posterior), genu (anterior), and central corpus callosal volume. Age and education did not contribute significantly to the model. Lower nadir CD4 correlated with decreased splenium (p = 0.048, R = 0.712) and genu (p = 0.040, R = 0.730) volumes in ApoE4 carriers only.
Conclusions: HIV-seropositive individuals possessing at least one ApoE4 allele are more vulnerable to effects of low nadir CD4 count, which may contribute to region-specific corpus callosum atrophy and thereby to cognitive impairment. Early ART may be more vital for these patients than for those without the allele.
Substance Use and HIV Infection: Neurocognitive Effect, the CHARTER Cohort: Substance use was not associated with compromised neuropsychological function at baseline in this HIV+ cohort when important co-factors were considered. This suggests that historic substance use and acute stimulant use do not require special consideration in cross sectional analyses of neuropsychological function in neuro-AIDS research.
Desiree Byrd*1, S Morgello1, D Franklin2, R Heaton2, and I Grant2
1Mt Sinai Sch of Med, New York, NY, US and 2HIV Neurobehavioral Res Ctr, Univ of California, San Diego, US
Background: Illicit substance use is associated with abnormal cognition, and there are concerns that with HIV, substance use contributes to neuropsychological dysfunction. We hypothesized that in a large HIV+ cohort: that those with a history of substance use would demonstrate worse baseline neuropsychological function than those without; that effects would be greatest for those not on ARVs; and that cumulative lifetime dose of substance would be negatively associated with neuropsychological function.
Methods: Baseline data were taken from the central nervous system (CNS) HIV ARV Treatment Effects Research (CHART) study. A multi-method approach was used to determine substance use: either lifetime DSM IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) diagnosis of substance use disorder, or self-report of lifetime use, or positive urine toxicology. A comprehensive battery of neuropsychological tests determined neurocognition. Variables subjected to statistical covariance or group level matching included age, ethnicity, education, literacy, plasma and CSF HIV load, nadir CD4, ARV status, and depressive symptoms. No persons were acutely intoxicated or in active withdrawal.
Results:
We analyzed 1316 participants: 81% reported lifetime substance use and 73% met DSM IV criteria for lifetime abuse or dependence. In a subgroup of subjects carefully matched for important variables, a MANCOVA of neuropsychological summary scores, co-varying for urine toxicology stimulants (cocaine or methamphetamine) and depression revealed no significant effect of substance use (F(8, 505) = 1.48, p = 0.145)..
Similarly, substance use had no effect on the proportional functional dependence or number of functional complaints. These results did not change when inclusion was restricted to those with DSM IV substance use disorders, or when ARV status was considered. Nonparametric correlational analyses of quantified lifetime substance use exposure with neuropsychological function demonstrated no significant relationships and did not vary by ARV status. Subjects with positive urine toxicology stimulants were compared to a matched group with negative urine toxicology. Participants with positive urine toxicology performed significantly better on verbal tests (F(1, 437) = 7.95, p <0.01) with no significant performance differences in other neuropsychological domains.
Conclusions: Substance use was not associated with compromised neuropsychological function at baseline in this HIV+ cohort when important co-factors were considered. The absence of relationship remained when substance use was determined by syndromic use, "casual" use, or urine toxicology, and did not vary by ARV status. This suggests that historic substance use and acute stimulant use do not require special consideration in cross sectional analyses of neuropsychological function in neuro-AIDS research.
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