CROI 2016 Abstract eBook

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Oral Abstracts

Conclusions: Higher PBMC mtDNA content was associated with worse neurocognitive performance in HIV+ adults, although PBMC mtDNA content was lower with older age. Higher mtDNA content can be caused by increased replication in response to mitochondrial dysfunction, indicating a connection between neurocognitive impairment and a systemic decrease of mitochondrial function observable in PBMCs. Associations with CSF biomarkers indicate that CSF free mtDNA may mediate neuroinflammation during HIV infection. 145 Lipid Profiles and APOE4 Allele Impact Midlife Cognitive Decline in HIV+Men on ART Shibani S. Mukerji 1 ; Joseph Locascio 1 ;Vikas Misra 2 ; Lorenz David 2 ; Alexander Holman 3 ; Anupriya Dutta 2 ; Sudhir Penugonda 4 ; StevenWolinsky 4 ; Dana Gabuzda 2 1 Massachusetts General Hosp, Boston, MA, USA; 2 Dana-Farber Cancer Inst, Boston, MA, USA; 3 Dana-Farber Cancer Inst, Brookline, MA, USA; 4 Northwestern Univ, Feinberg Sch of Med, Chicago, IL, USA Background: Dyslipidemia and the ApolipoproteinE4 (APOε4) allele are recognized risk factors for cognitive decline in the general population, but how these risks are modified by HIV serostatus is unclear. This longitudinal study examined relationships between lipid profiles, APOε4 allele, and cognitive decline in a cohort of ART-treated HIV+men over age 50. Methods: In a nested case-control study from the Multicenter AIDS Cohort Study (MACS) public data, 273 HIV+men (50-65 years, without active heavy drug use, ≥2 visits with neurocognitive testing between 1996-2010, baseline VL<400 copies/ml, and continuous ART use ≥95% visits) were matched by baseline age, race, education, smoking, and alcohol use to 516 HIV- controls using R MatchIt. A composite measure of global cognition was created from 15 cognitive tests in 6 domains. The association between HIV serostatus, time-varying lipid markers (total cholesterol, LDL, HDL, and triglycerides), APOE genotype (n=344), and cognitive decline was examined using multivariable mixed effects models, adjusting for baseline age, CD4 count, IQ, CES-D, and smoking. Results: The median baseline age of participants was 51 years (IQR: 50-54); 81%white, 89% had education >12 years; heavy smoking (21% vs 17%; p=0.3) and alcohol use (17% vs 11%; p=0.2) were similar between HIV+ and HIV- men, respectively. HIV+men had baseline median CD4 count of 514 cells/uL, and 70%were virally suppressed in study (<50 copies/ml with ≤2 blips, blip <400 copies/ml). Higher total cholesterol, LDL, and triglycerides, and lower HDL levels were associated with faster rate of cognitive decline in HIV+ men in mixed effects models (p<0.05). There was no significant relationship between HIV serostatus and baseline cognitive score, suggesting that cognitive decline diverged after study entry. In mixed models adjusted for the same terms, APOε4 allele was associated with accelerated cognitive decline in HIV+men (p=0.01). In all models, CES-D≥ 16 and older baseline age were associated with lower cognitive scores; IQ was associated with higher cognitive scores. Conclusions: Measures of lipid markers were associated with faster rates of cognitive decline among ART-treated HIV+men over the age of 50. HIV+ APOε4 carriers are at substantial risk for accelerated midlife cognitive decline, and are predicted to decline at younger ages than HIV- carriers. These findings suggest pathways affecting lipid metabolismmay accelerate cognitive aging among older HIV+ individuals.

Oral Abstracts

146 Paroxetine and Fluconazole Therapy for HAND: A Double-Blind, Placebo-Controlled Trial Ned Sacktor 1 ; Richard L. Skolasky 1 ; Norman Haughey 1 ; Cynthia Munro 1 ; Richard Moxley 1 ; Joseph Steiner 2 ; Avindra Nath 2 ; Justin McArthur 1 1 Johns Hopkins Univ Sch of Med, Baltimore, MD, USA; 2 NIH, Bethesda, MD, USA Background: Paroxetine and fluconazole have potent neuroprotective effects in an in vitro model of mitochondrial stress and HIV-protein mediated neural damage. We studied the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). Methods: HIV+ individuals with cognitive impairment were enrolled in a 24 week randomized double-blind, placebo-controlled 2x2 factorial design study. Participants were randomly assigned to 1 of 4 groups: 1) paroxetine 20mg/day orally, 2) fluconazole 100mg every 12 hours orally, 3) paroxetine 20mg/day and fluconazole 100mg every 12 hours, or 4) placebo. Safety, tolerability, and efficacy, including neuropsychological testing and cerebrospinal fluid (CSF) lipid markers of oxidative stress, were evaluated. Change in neuropsychological test performance and oxidative stress markers was modeled using a general linear regression model. Results: 45 HIV+ individuals were enrolled. There was no difference in adverse events among the treatment arms. HIV+ individuals in the paroxetine arms (alone or in combination with fluconazole), compared to the no paroxetine arms (placebo or fluconazole alone) showed a benefit in cognitive performance in the NPZ8 summary measure of 8 neuropsychological tests (NPZ8 mean change = 0.15 vs -0.33, p=0.010), and a computerized test of executive function (Cal Cap sequential mean change = 0.46 vs 0.06, p=0.002), after adjusting for depression symptomatology and baseline NPZ8 in as-treated analyses. There was no difference in change in depression symptomatology or CSF lipid markers of oxidative stress between paroxetine and no-paroxetine arms. HIV+ individuals in the fluconazole arms (alone or in combination with paroxetine) compared to the no fluconazole arms (placebo or paroxetine alone) did not show a benefit in cognitive performance, but fluconazole was associated with a decrease in CSF ceramide 18:0 (p=0.039) after adjustment for baseline ceramide level in intent-to-treat analyses. Conclusions: Paroxetine and fluconazole in HIV+ individuals were safe and well tolerated. Paroxetine may be associated with cognitive improvement, even after adjusting for depression symptoms. Fluconazole was associated with a decrease in a lipid marker of oxidative stress. Studies of additional outcome measures including other CSF markers of oxidative stress and functional neuroimaging are underway to examine specific mechanisms of neuroprotection.


CROI 2016

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