CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

440 HIV-1 Replication in the CNS Is AssociatedWith Increased Neurocognitive Impairment Sarah B. Joseph 1 ; Laura Kincer 1 ; Natalie M. Bowman 1 ; Prema Menezes 1 ; Kevin Robertson 1 ; Albert M. Anderson 2 ; DavidW. Loring 3 ; Joseph J. Eron 1 ; RichardW. Price 4 ; Ronald Swanstrom 1 1 University of North Carolina, Chapel Hill, Chapel Hill, NC, US; 2 Emory University, Atlanta, GA, US; 3 Emory University, Atlanta, GA, US; 4 University of California San Francisco, San Francisco, CA, US; 5 University of North Carolina, Chapel Hill, Chapel Hill,, NC, US Background: HIV-infected individuals are reported to have higher levels of neurocognitive impairment than HIV-negative controls. We examined the association between independent HIV-1 replication in the CNS and neurocognitive impairment. Methods: We used cerebrospinal fluid (CSF) and blood plasma samples from 40 subjects off antiretroviral therapy (ART) to characterize viral populations in the CNS and blood. Subjects were enrolled in 1 of 4 cohorts. Two cohorts enrolled subjects based on neurological symptoms and two enrolled subjects based on CD4 count and viral load. All subjects had neurocognitive assessments. cDNA was generated from viral RNA and partial env genes were amplified and sequenced by Illumina deep sequencing with Primer ID to quantify the number of templates examined (Fig. 1A); and/or full length env genes were amplified and sequenced by single genome amplification (SGA)(Fig. 1B). Pseudotyped viruses were generated from cloned, full-length env genes and used in entry assays to determine whether Env proteins were well-adapted to entering cells expressing low levels of CD4 (i.e. macrophage-tropic; Fig 1C). Results: Based on formal neurocognitive assessments, subjects were classified into three groups with increasing levels of neurocognitive impairment: 1) normal (N=7), 2) mild neurocognitive disorder or asymptomatic neurocognitive impairment (N=10), and 3) HIV-associated dementia (N=23). The observation of genetically distinct, viral lineages in the CSF was evidence of ongoing replication in that compartment, and these lineages were considered compartmentalized (Fig. 1A and 1B). Increasing neurocognitive impairment was positively associated with compartmentalization (exact trend test, p=0.04). For 71% of subjects with compartmentalized HIV-1 in their CSF, this virus was also macrophage-tropic, and thus compartmentalization was significantly associated with macrophage tropism (fisher’s exact test, p= 0.001).

Conclusions: HIV-1 replication in the CNS is strongly associated with neurocognitive impairment and the majority of subjects with evidence of ongoing HIV-1 replication in the CNS have macrophage-tropic HIV-1 in that compartment. These results suggest that there may be a causal relationship between HIV-1 replication in macrophage-lineage cells in the CNS and neurocognitive symptoms in HIV-infected subjects off therapy. Antiretroviral therapy that fully suppresses viral replication in the CNS, particularly in macrophages, may be more likely to improve neurocognitive performance.

Poster Abstracts

TUESDAY, FEBRUARY 24, 2015 Session P-G2 Poster Session

Poster Hall

2:30 pm– 4:00 pm Optimizing ART for HAND Treatment and Prevention 441 Maraviroc-Enhanced CART Improves Cognition in Virally Suppressed HAND: A Pilot Study Thomas M. Gates 1 ; Lucette A. Cysique 2 ; Joga Chaganti 1 ; Krista J. Siefried 1 ; Bruce J. Brew 1 1 St Vincent’s Hospital, Sydney, Sydney, Australia; 2 Neuroscience Research Australia (NeuRA), Sydney, Australia

Background: HIV-associated neurocognitive disorders (HAND) occur despite viral suppression in blood and cerebrospinal fluid on combined antiretroviral therapy (CART). One therapeutic option may be CART enhancement with Maraviroc (MA) as MA can penetrate the Central Nervous System (CNS) and has dual antiretroviral/anti-inflammatory activity. Methods: 19 virally-suppressed HIV+males (M=53 years old) with formally diagnosed HAND were enrolled in a prospective, randomized, double observer-blinded, open-label pilot RCT. Two subjects failed screening. One subject withdrew for personal issues, 2 were lost to follow-up. Of 14 subjects completing all study visits, 9 were randomized to receive MA enhancement and 5 to continue on existing CART. 2 MA and 1 control subject had confirmed CXCR4-tropic virus in blood; 1 control had confirmed CCR5-tropic virus. HIV tropism status was unavailable for other subjects. Subjects completed neurocognitive (NR) testing assessing 5 cognitive domains at baseline, 6- and 12-months. Primary endpoint was NR change across study period (defined as a global z-score averaging each domain z-score correcting for age and gender). Secondary endpoints were 1 H-MR Spectroscopy (MRS) metabolite concentrations in the basal ganglia (BG) and frontal white matter (FWM) at Baseline and 12-months and quantified using LC Model. NR change was analyzed using mixed effect linear regression models with fixed effects: arm, time, arm*time interaction and subject as a random effect to account for attrition. In total, 38 subject visits were included in the analyses (MA: n=27; control: n=14). MRS change was analyzed using repeated measures ANOVA with same fixed effects. Trends p<.10 are reported as this represents pilot data in a small sample. Effect sizes Cohen’s d and β assist in interpretation of effect.

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CROI 2015