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Neuradapt: a prospective study concerning HIV-related neurocognitive impairment Matteo Vassallo* 1, Alexandra Harvey-Langton 1, Christian Pradier 1, Sara Ferrando 1, Jaqueline Cottalorda 1, Christophe Caissotti 1, Jacques Durant 1, Gregoire Malandain 2, Stephane Chanalet 3, Pierre Dellamonica 1 1- L’Archet Hospital, Ctr Hosp Univ Nice, France; 2- INRIA, Sophia Antipolis, France; 3- Pasteur Hosp, Ctr Hosp Univ Nice, France The HIV Neurobehavioral Research Center (HNRC) modified the AAN criteria in December 2007, proposing three conditions for defining NCI: 1.HIV-associated asymptomatic neurocognitive impairment (ANI), including all patients with impairment in at least two ability domains, documented by performance of at least 1.0 SD below the mean for age-education appropriate norms on standardized neuropsychological tests, without interference in everyday functioning. 2.HIV-1-associated minor neurocognitive disorder (MCD), including patients with at least 2 ability domains 1.0 SD below the mean and a mild interference in daily functioning. 3.HIV-1-associated dementia (HAD), with patients having at least 2 SD difference or greater below the mean in two ability domains, with a marked interference in daily activities. [1,2] Recently another category of patients has been introduced, with only one cognitive abnormality and defining it as a neuropsychological deficit (ND).  These patients do not enter in the present definition of NCI and little is known about the frequency of this condition and its clinical relevance. Our aim was to evaluate neurocognitive functioning on HIV-1 infected populations using the HNRC classification and to correlate results to the other relevant parameters. During a second phase, we will correlate results to imaging. Study design and participants: Neuradapt © is an ongoing prospective study of NCI prevalence among HIV-1 infected patients followed in Nice University Hospital. We randomly selected HIV-1 seropositive patients among subjects followed in our Department. No exclusion limits were defined concerning CD4 cell count or on HIV viral load. Exclusion criteria were: previous diagnosis of HIV-related NCI, active opportunistic infection, modification of psychotic therapy in the last 3 weeks, previous stroke, endocarditis or meningo-encephalitis. Neuropsychological analysis: Each patient performed neuropsychological (NP) tests exploring a wide spectrum of cognitive domains: verbal/language, attention/working memory, abstraction/executive functions, memory (learning and recall), speed of information processing, sensory/perceptual and motor skills. The score for each test was adjusted for age, gender and education. According to the classification proposed by the HNRC, we identified 5 groups of patients: Group 1, with normal NP testing Group 2, with at least 2 SD below the mean in one cognitive test or at least 1 SD below the mean in more than 1 test exploring the same domain. These results defined the condition of ND Group 3, including patients with criteria for ANI Group 4, including patients with MCD Group 5, considering patients with HAD Demographic parameters and background measurements: For each patient we considered the following parameters, in order to correlate results to NP testing classification: age, gender, education, co-morbid conditions (hypertension, smoke, dyslipidemia, use of illicit drugs, diabetes), use of psychotropic molecules (benzodiazepines, antidepressants, carbamates and anti-epileptic drugs), CD4 cell count at inclusion and at the nadir, HIV-RNA viral load, DNA-proviral load, markers of viral hepatitis, immune activation parameters (CD4+CD38+, CD8+CD38+ CD4+HLA-DR and CD8+HLA-DR), type of antiretroviral therapy at inclusion and CNS drug penetration-effectiveness (CPE) score  Co-infection with hepatitis C virus (HCV) : In case of co-infection with C hepatitis, we quantified HCV viral load at inclusion in the study. Consequently, patients were divided into 3 categories: 1) Negative for HCV infection 2) Positive for HCV infection with detectable viral load 3) Positive for HCV infection with undetectable viral load. Analysis of CSF: Patients with NP testing results defining NCI (i.e. groups 3, 4 and 5) were offered to undergo a lumbar puncture for CSF analysis. A total of approximately 5 mL of CSF was obtained for each patient; subjects were excluded if CSF showed > 20 red blood cells per μL. In particular, we considered the following CSF parameters: white cells count, proteins, glucose and HIV viral load with viral genotyping (when it was possible). Statistical analysis: The associations between NP testing results (Gr 1 vs Gr 2 vs Gr 3) and potential risk factors have been studied in univariate analyses using the ² test for categorical variables and Kruskal-Wallis test for continuous ones. We used a multivariate logistic regression model to test de relationship between NP testing results and HCV co-infection. The odds ratios (OR) and their 95% confidence interval (CI 95%) were estimated before and after adjustment on all the potential confounding factors. The p-values were considered statistically significant in the analyses when below 0.05. Statistical analyses were performed using SPSS software. Results CHU Nice Group 2 accounted for 42% of patients, while prevalence of NCI (i.e. groups 3, 4 and 5) was 23%. Only 35% of patients had normal NP testing. (Figure 1) Main impairments were represented by attention/working memory, recall memory and speed of information processing. In 6% of patients impairments concerned learning memory, suggesting a cortical profile. (Figure 2) We did not find any significant differences for age or co-morbid conditions between groups of NP testing. HCV infection and antidepressants were associated with ND or NCI. More precisely, HCV co-infection showed a correlation with the degree of NP impairment (12.5% for normal NP testing vs 24% for ND vs 33% for NCI, p=0.05). Even excluding patients with antidepressants, HCV was still a risk factor for abnormal NP testing results. HCV viral load did not differ between groups of NP testing. (Table 1) Other parameters showing significant differences among classes at NP testing were a previous AIDS-defining condition, current therapy with PI, and CD8 cell count (Table 1). Multivariate logistic regression analysis showed that HCV infection was an independent risk factor for abnormal NP testing results (i.e. ND or NCI) (OR=2.64, IC95% [1.07; 6.53], p=0.035). Regarding CSF analysis, 17 patients underwent lumbar puncture: in 13 out of 17 cases, HIV viral load was below 40 cp/ml and in 12/13 patients it correlated with an undetectable plasmatic viral load. In 4 cases viral load in CSF was detectable, with the following values: 3250 cp/ml, 2400 cp/ml, 280 cp/ml and 90000 cp/ml. Genotyping was possible for 3 of 4 patients and results were perfectly comparable to the genotype from plasma. Moreover, 2 of 4 patients with detectable viral load in the CSF were not on antiretroviral therapy and in the other two patients compliance was poor, as proved by the detectable viral load in the plasma and by wild-type plasmatic genotype. (Table 2) Figure 2: Percentage of cognitive impairments Figure 1: NP testing results Patient numberAgeCurrent HAARTCD4 cell countViral load in plasma (cp/ml) Viral load in CSF (cp/ml) 1462 NRTI + 1 NNRTI3085203250 2492 NRTI + 1 boosted PI456<40 3422 NRTI + 1 boosted PI + Enfuvirtide18390002400 4432 NRTI + 1 NNRTI352<40 5582 NRTI + 1 boosted PI347<40 6482 NRTI + 2 boosted PIs356<40 7582 NRTI + 1 boosted PI672<40 8672 NRTI + 1 boosted PI663<40 9332 NRTI + 1 boosted PI104<40 10392 NRTI + 1 boosted PI962<40 11412 NRTI + 1 boosted PI764<40 12442 NRTI + 1 boosted PI667<40 13602 NRTI + 1 boosted PI450<40 1443No HAART64243000280 1540No HAART2403200090000 16452 NRTI + 1 NNRTI1014<40 17442 NRTI + 1 PI7021500<40 Table 2: Comparison of plasma and CSF viral load Our results confirmed previous studies concerning the current incidence of neurocognitive disorders, estimated at 27% by Robertson et al.  As previously described, memory impairments could also have cortical features, suggesting an Alzheimer profile. On the contrary, our tests revealed an unexpectedly high percentage of patients with ND. To our knowledge, no other studies performed an analysis of prevalence of ND in an HIV seropositive population. The clinical relevance of ND is still not explained, but the high proportion of patients affected needs further evaluation and probably closer follow- up. Previous articles showed that HCV co-infection is linked to a higher risk of neurocognitive disorders  and our study showed that its prevalence increases with the degree of impairment at NP testing. HCV co-infection was confirmed to be an independent risk factor for impairment, even excluding the possible impact of psychotropic molecules on NP testing results. Among other risk factors, we found significant differences between groups for previous AIDS-defining condition, CD8 cell count and PI use at inclusion. However, no speculation could be put forward about a possible role of PIs for increasing risks of NCI, because our analysis considered only current therapy at inclusion in the study. Only follow-up of patients regarding NP testing changes could elucidate these aspects. Analysis of lumbar puncture shows that an undetectable value of plasmatic HIV viral load corresponds to the same result in the CSF, despite NP testing abnormal results. Only in one patient we found a discrepancy in viral load between the two compartments. If confirmed by the analysis of larger cohorts of patients, it could signify that for patients with NCI, we need other parameters than HIV viral load in the CSF for deciding if a change of HAART is suitable. References: 1) Janssen RS, Cornblath DR, Epstein LG et al. – Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection. Report of a Working Group of the American Academy of neurology AIDS Task force. Neurology 1991;778-785 2) Antinori A., Arendt G., Becker J.T. et al, Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69;1789-1799 3) Letendre S – New approaches to diagnosis and management of neurological complications in the HAART era 4) Letendre S., Marquie-Beck J., Capparelli E. et al. – Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65(1):65-70 5) Robertson KR, Smurzynski M, Parsons TD et al. – The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 2007, 21:1915-1921 6) Clifford DB, Evans SR, Yang et al. – The neuropsychological and neurological impact of hepatitis C virus co-infection in HIV-infected subjects. AIDS 2005; 19:S64-S71 Background Normal NP testing Neuropsychological deficit Neurocognitive impairment (ANI + MCD+ HAD ) p-value N (%) or median (IQR) Use of psychotropic molecules Benzodiazepines5 (8.9%)5 (7.6%)8 (22.2%)0.06 Antidepressants1 (1.8%)8 (12.1%)0 (0.0%)0.01 Other co-morbidities Diabetes1 (1.8%)0 (0%)1 (1%)0.44 Hypertension1 (1.8%)6 (9.1%)4 (11.1%)0.15 HIV RNA (log10 copies/ml) at inclusion 1.60 (1.60-2.89)1.60 (1.60-2.62)1.60 (1.60-2.13)0.85 CD4 count (cells/mm3)480 (374-729)528 (398-686)551 (338-767)0.89 CD8 count (cells/lmm3)774 (652-1073)767 (581-1176)1089 (867-1315)0.02 Nadir CD4 count (cells/mm3)208 (109-378)278 (156-364)188 (33-355)0.44 Latest lipid measurements: HDL cholesterol (mmol/L); median (IQR)1.20 (0.98-1.40)1.27 (0.96-1.67)1.20 (0.9-1.30)0.29 LDL cholesterol (mmol/L); median (IQR)3.40 (2.60-3.80)3.13 (2.57-3.69)3.50 (2.70-3.80)0.71 Antiretroviral therapy at inclusion NTRI44 (78.6%)50 (75.8%)34 (94.4%)0.06 NNRTIs22 (39.3%)22 (33.3%)8 (22.2%)0.23 PIs23 (41.1%)30 (45.5%)24 (66.7%)0.04 Antiretroviral CSF Penetration Score0.751.0 0.32 Normal NP testing Neuro- psychological deficit Neurocognitive impairment (ANI + MCD+ HAD ) p-value N (%) or median (IQR) Number of patients 566636 Male sex46 (82.1%)50 (75.8%)28 (77.8%)0.69 Age (years)43 (37-51)43 (38-48)45 (41-53) Risk group Homosexual IDU Heterosexual Other 28 (50.0%) 17 (30.4%) 8 (14.3%) 3 (5.4%) 26 (39.4%) 23 (34.8%) 9 (13.6%) 8 (12.1%) 13 (36.1%) 10 (27.8%) 3 (8.3%) 0.38 Prior AIDS event 12 (21.4%)13 (19.7%) 16 (44.4%)0.01 Time since HIV infection (year) 12 (4-17)13 (7-17) 15 (8-20)0.11 Hepatitis C positive 7 (12.5%)16 (24.2%) 12 (33.3%)0.05 Hepatitis C negative49 (90.7%)50 (78.1%)24 (68.6%) positive with undetectable viral load4 (1.9%)9 (14.1%)6 (17.1%) positive with detectable viral load4 (7.4%)5 (7.8%)5 (14.3%)0.07 Current smoker 9 (18.4%)19 (31.7%)11 (40.7%)0.09 From December 2007 to January 2009, 158 patients (79% male, mean age 44 years, mean CD4 cell count 558 cc/mm3) were included. (Table 1) Table 1: patient characteristics Table 1 Abstract Methods Conclusions Po 464 Background: The HIV Neurobehavioral Research Center (HNRC) recently added the concept of HIV-related asymptomatic neurocognitive impairment (ANI) to HIV-associated dementia (HAD) and minor cognitive disorders (MCD). These 3 categories define the current diagnosis of HIV-associated neurocognitive impairment (NCI). Neuropsychological deficit (ND) includes patients with impairment in only one cognitive domain, not included in the definition of NCI. Little is known of the frequency and clinical relevance of ND. Our aim is to firstly evaluate its prevalence among the HIV-infected population and then correlate the results to imaging. Methods: Neuradapt© is an ongoing, prospective study of NCI prevalence among HIV-1 infected patients followed in Nice University Hospital. From December 2007, we randomly selected patients to undergo neuropsychological (NP) testing. We used the HNRC classification (Normal tests, ND, ANI, MCD, and HAD). Test score was adjusted for age, gender and education. CD4 count, HIV-RNA viral load (VL), DNA-proviral load, viral hepatitis, immune activation markers (CD4+CD38+, CD8+CD38+) and cerebral multi-spectral MRI were explored. We also considered current use of psychotropic molecules and HCV therapy, type of antiretroviral therapy at inclusion and CNS drug penetration-effectiveness (CPE). Results: From December 2007 to September 2008, 158 patients (78% male, mean age 44 years, 86% on HAART, mean CD4 cell count 558/mL, 54 % of patients with VL <40 cp/mL, 22% HCV co-infected) were included; 11% were on benzodiazepines and 6% on antidepressants. HNI accounted for 23% of patients (ANI 12%, MCD 8% and HAD 3%). However, 42% of patients presented with ND. Thus only 35% had normal tests. HCV infection (p=0.05) and antidepressants (p=0.01) were associated with ND or HNI. Even excluding antidepressants, HCV was still a risk factor for abnormal NP testing results. Other parameters showing significant differences among classes at NP testing were a previous AIDS-defining condition, current therapy with PI, and CD8 cell count. Multivariate analysis showed only HCV co-infection to be an independent risk factor for abnormal NP performance (p =0.035). Conclusion: Up to 65% of subjects have abnormal NP scores and ND accounted for 42% of subjects in our series. Hepatitis C appears to be a risk factor regardless of the degree of cognitive impairment. The clinical relevance of ND is not known, but the high proportion of subjects needs further evaluation by imaging.
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