CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

147

MVC and TDF Reduce Neurocognitive Impairment in Initial ART: ACTG A5303 Kevin R. Robertson 1 ; Sachiko Miyahara 2 ; Anthony Lee 2 ;ToddT. Brown 3 ; Ellen S. Chan 2 ; Baiba Berzins 4 ; David Rusin 5 ; Joseph J. Eron 1 ; BabafemiTaiwo 6 ; for the AIDS ClinicalTrials Group Team 5303 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2 Harvard Univ, Boston, MA, USA; 3 Johns Hopkins Univ, Baltimore, MD, USA; 4 Northwestern Univ, Chicago, IL, USA; 5 Frontier Sci & Tech Rsr Fndn, Inc, Amherst, NY, USA; 6 Feinberg Sch of Med, Northwestern Univ, Chicago, IL, USA Background: HIV associated neurocognitive impairment remains problematic despite suppressive antiretroviral therapy (ART). Potential mechanisms include persistent low level HIV infection in the central nervous system (CNS) which sustains inflammation that causes neuronal damage. The neurocognitive effects of maraviroc (MVC), a CCR5 coreceptor inhibitor with uncertain immune modulatory effects and potentially better CNS penetration relative to tenofovir disoproxil fumarate (TDF), are unknown. We investigated neurocognitive changes with MVC- vs TDF-containing ART in ACTG A5303 where both regimens were shown to have similar efficacy in suppressing plasma HIV viremia. Methods: ACTG A5303 was a double-blind, placebo-controlled, multicenter, 48 week study conducted in the US. ART naïve participants with CCR5 tropic HIV-1 and viral load (VL) >1000 copies/mL were randomized 1:1 to MVC 150mg QD + TDF placebo or TDF 300mg QD +MVC placebo (plus DRV+ RTV+FTC); stratified by VL< / ≥100,000 c/mL and age < / ≥30 yrs. The neuropsychological (NP) battery of 15 tests done at baseline, week 24 and week 48 assessed Language, Attention, Executive, Learning, Memory, Speed of Processing, and Fine motor domains, and were standardized into z scores then converted into deficit scores (DS) and a global deficit score (GDS). The 48-week changes from baseline in the NP scores and the GDS were compared by Wilcoxon or Kruskal-Wallis test between arms, and among baseline impairment groups (classified as normal, mild (2 DS ≥1) and moderate (2 DS ≥2)). Results: Of the 230 baseline participants (MVC=119, TDF=111), the arms were comparable for: 9%were female; median age was 33 yrs, 44%White, 31% Black, 22% Hispanic; >12 years education 70%; median VL was 4.5 log 10 c/mL and CD4 count was 390 cells/mm 3 . There were no significant differences in GDS between the arms at baseline (median (IQR) MVC 0.33 (0.07, 0.73); TDF 0.33 (0.13, 0.64)).There were no significant differences between arms for the 48-week changes in standardized NP scores and the GDS (p>0.05; Figure 1A). Those with moderate impairment at baseline experienced greater ART-mediated declines in GDS (median (IQR) -0.4 (-0.7, -0.2)) than those with mild (-0.2 (-0.3, -0.1)) or no impairment (0 (-0.1, 0.1), p<0.001, Figure 1B). Conclusions: Neurocognitive functioning improved with effective ART, and was comparable in those treated with MVC or TDF in combination with DRV/RTV+FTC. The higher the baseline impairment, the greater the neurocognitive improvement and response to ART.

Oral Abstracts

148 Brain MRI Changes AssociatedWith Poorer Cognitive Function in Treated HIV Infection Jonathan Underwood 1 ; James H. Cole 1 ; MatthanW. Caan 2 ; David J. Sharp 1 ; Davide De Francesco 3 ; Robert Leech 1 ; Caroline Sabin 3 ; Charles B. Majoie 2 ; Peter Reiss 4 ; AlanWinston 5 ; for the Co-morBidity in Relation to Aids (COBRA) Collaboration 1 Imperial Coll London, London, UK; 2 Academic Med Cntr, Amsterdam, Netherlands; 3 Univ Coll London, London, UK; 4 Amsterdam Inst for Global Hlth and Develop, Amsterdam, Netherlands; 5 Imperial Coll of Sci, Tech and Med, London, UK Background: Grey and white matter (GM and WM) abnormalities have been reported in HIV-positive subjects. However, data are sparse in virologically suppressed cohorts compared with appropriate control populations. Methods: We assessed cognitive function across 6 domains, brain tissue volumes (T1 structural MRI) and WMmicrostructure (diffusion weighted MRI) in 134 HIV-positive individuals on suppressive cART (median (range) 56 (45-82) years) and 79 demographically comparable HIV-uninfected subjects (57 (47-80) years). To delineate localised differences in brain structure between HIV-positive subjects and controls, whole brain (voxelwise) analyses of GM volume (GMV), WM volume (WMV), fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD and RD respectively) were performed using permutation testing, adjusting for age, intracranial volume and scanner type. To relate imaging findings to cognitive measures, GMV, FA and cognitive domain T scores were integrated using the kmeans clustering statistical method. Results: Significantly lower T-scores, representing poorer cognitive function, were evident in 4/6 cognitive domains. Median T scores in HIV-positive subjects vs. controls were: attention: 50.2 vs. 56.8; executive function: 49.3 vs. 52.3; motor function: 48.5 vs. 51.2; processing speed: 51.2 vs. 54.6 (p≤0.01 for all); language: 52.6 vs. 53.2 and memory: 56.7 vs. 56.2 (p=0.42 for both). Voxelwise analyses demonstrated significantly lower GMV, principally in the intra- and supracalcarine cortices and the lingual gyrus (35%, 27% and 13% voxels affected), in HIV- positive subjects vs. controls. Additionally, widespread abnormalities in white matter microstructure (FA, MD, RD but not AD) but not WMV were evident in HIV-positive individuals vs. controls. Subjects optimally clustered into a higher GMV/FA cluster (n=116, cluster means: GMV 701 mL, FA 0.492) and a lower GMV/FA cluster (n=88, cluster means: GMV 614 mL, FA 0.467). HIV-positive subjects were more likely to be members of the lower GMV/FA cluster compared with controls, 52.3% vs. 27.0% (Χ 2 =11.3, p<0.001). This cluster also exhibited poorer cognitive function (figure 1). Conclusions: Grey matter atrophy and white matter microstructural abnormalities suggestive of demyelination were evident in HIV-positive subjects compared to controls. These changes were in spite of fully suppressive cART and were associated with poorer cognitive function. Future work to understand the underlying pathogenesis of these imaging changes is warranted.

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CROI 2016