CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

(n=10) in the CHI subjects, and HIV RNA levels and soluble biomarkers were measured at each visit. Cross-sectional analyses employed the Mann-Whitney and Spearman tests; paired analyses were used to compare subjects across time points. Results: At initial sampling, median CD4 T cell count was 401 and 228 cells/uL in the AHI and CHI groups, respectively (p<0.0001). At baseline (median 18 days post estimated date of infection in AHI and unknown duration in CHI), median CSF YKL-40 was elevated in CHI (96,844 ng/L) compared with AHI subjects (80,754 ng/L; p=0.01) and controls (86,612 ng/L; p=0.07). In CHI but not AHI subjects, YKL-40 correlated with CSF neurofilament light chain (NFL; r=0.56, p<0.001), CSF neopterin (r=0.51, p=0.003), and CSF interferon- gamma-inducible protein 10 (IP-10; r=0.44, p=0.010). There were no correlations with HIV RNA or other soluble immune biomarkers in either group. After at >6 months of sustained cART (24 weeks in AHI and 48 weeks in CHI), the AHI group had a lower median CSF YKL-40 than CHI subjects (66,130 ng/L versus 87,414 ng/L, p=0.003). Conclusions: Elevations in CSF YKL-40 suggestive of reactive astrocytes and microglial activation were present in CHI but not AHI subjects at baseline. YKL-40 declined after cART in CHI subjects, but remained elevated after treatment as compared to values in AHI participants after cART. YKL-40 correlation with NFL supports a role for astrocyte and/or microglial activation during CHI in neuronal injury that might be mitigated by early cART initiation. 474 CNS Immunoactivation and Neuronal Damage in Patients With Progressive Neurocognitive Impairment Arvid Edén 1 ; Donald Franklin 2 ; Henrik Zetterberg 1 ; Dietmar Fuchs 3 ; Robert Heaton 2 ; Scott Letendre 2 ;Thomas Marcotte 2 ; Richard Price 4 ; Igor Grant 2 ; Magnus Gisslén 1 1 University of Gothenburg, Gothenburg, Sweden; 2 University of California San Diego, San Diego, CA, US; 3 Innsbruck Medical University, Innsbruck, Austria; 4 University of California San Francisco, San Francisco, CA, US Background: Although HIV-associated neurocognitive disorders (HAND) remain prevalent, the clinical significance is unclear. A recent report indicates a higher risk of symptomatic progression in subjects with asymptomatic neurocognitive impairment (ANI) than in unimpaired subjects. In a previous cross sectional analysis, we found that subjects with neurocognitive impairment (NCI) had increased cerebrospinal fluid (CSF) levels of neopterin but not neurofilament protein light subunit (NFL) compared to unimpaired subjects. Here, we investigated if a decline in neurocognitive performance (NP) was associated with ongoing neuronal damage measured by CSF NFL in a well characterized cohort of virally suppressed subjects. Methods: Subjects on antiretroviral therapy (ART) with plasma HIV-1 RNA <50 c/ml without significant confounding conditions were identified from longitudinal studies (CHARTER and HNRC). Standardized NP testing was performed on two separate occasions. Subjects were classified as NP normal (NPN) or NCI (including subjects with ANI or mild neurocognitive disorder (MND)). According to NP test stability, subjects were categorized as NP stable or NP decline. CSF NFL was measured by enzymatic 2-site quantitative immunoassay (UmanDiagnostics, Umea, Sweden). CSF neopterin was measured by ELISA. The difference in CSF biomarkers between NCI and NPN were analyzed using a mixed effects model adjusting for age. Mann Whitney test was used to explore change in biomarkers according to NP progress. Correlations were explored using Pearson correlation. Results: 100 (91%male) subjects were included in the analysis, 29 NPN and 71 with NCI (ANI=38; MND=33). 32 subjects (all in the NCI-group) had a NP decline from baseline to follow up. We found no differences in change of CSF NFL or neopterin in subjects with NP decline compared to NP stable subjects. However, the NCI-group had 17 % higher age- adjusted NFL (P=0.08) and 27 % higher neopterin (P=0.03) compared to the NPN-group. Neopterin was significantly correlated with NFL in the NCI-group (r=0.38; P=0.001), but not in the NPN-group (R=-0.17; P=0.4). Conclusions: We did not find any difference in CSF NFL or neopterin in virologically suppressed subjects with progressive neurocognitive impairment compared to subjects without functional decline. However, the correlation found between CSF neopterin and NFL in subjects with NCI indicates an association between immune activation, neuronal damage and neurocognitive impairment that needs to be further characterized. 475 Endothelial Function and CNS Measures in Primary HIV Infection Pre and Post Early ART Background: HIV infection, vascular perturbation, and central nervous system (CNS) dysfunction may associate through common pathogenic pathways of inflammation observed even in antiretroviral therapy (ART)-controlled HIV infection. We examined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and biomarker of endothelial dysfunction in participants recruited during primary HIV infection (PHI, < 365 days post infection, DPI), examining associations between ADMA and measures of systemic and CNS perturbation before and after ART and over time. Methods: 25 ART-naïve PHI individuals were assessed at baseline and at an interval 6-12 months after initiating ART. Assessments included clinical blood measures, an 11 test neuropsychological battery (summarized as total Z and 4 test NPZ-4), and CSF total white blood cell count and albumin ratio. ADMA levels in PHI subjects were compared with published values in HIV-uninfected controls (HIV-, n=50) and chronically infected subjects (median 13 years duration infection) with viral suppression on ART (n=148) measured in the same laboratory. Nonparametric statistics were employed for analysis. Results: PHI subjects were assessed at baseline at median 139 (IQR 54, 182) DPI and subsequently at median 281 (202, 372.5) days after ART initiated 256 (133, 744) DPI. At baseline, PHI participants had higher median ADMA 0.70 (0.62, 0.82) m M than historical HIV- (0.44 μ M, 0.38, 0.46) and chronically HIV-infected subjects on ART (0.46 μ M, 0.41, 0.52, p < 0.0001 for each comparison). ADMA levels in PHI did not change from baseline to post-ART (p=0.87), and remained elevated compared with HIV- and chronic, on-ART comparisons (p<0.0001 for each). In PHI, ADMA did not associate with total Z or NPZ4 pre- or post-ART, nor correlate over time with respect to change in each measure. Of laboratory measures, pre-ART ADMA associated with blood CD8+ T cell count (p=0.05), as previously reported in chronic infection. Sebastian Urday 1 ; Zaina Zayyad 1 ; Julia Peterson 2 ; Felicia C. Chow 2 ; Kevin R. Robertson 3 ; Richard Price 2 ; Priscilla Hsue 2 ; Serena Spudich 1 1 Yale University, New Haven, CT, US; 2 University of California San Francisco, San Francisco, CA, US; 3 University of North Carolina, Chapel Hill, NC, US

Poster Abstracts

322

CROI 2015