CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

459 Predictors of Cognitive Performance Among HIV-Infected Patients in East Africa Victor G. Valcour 1 ; Francis Kiweewa 2 ; Rosemary Namagembe 2 ; Rither Langat 3 ; Samoel Khamadi 4 ; Kyra Hansson 1 ; Christina S. Polyak 5 ; Julie Ake 5 On behalf of the RV329 AFRICOS StudyTeam 1 University of California San Francisco, San Francisco, CA, US; 2 Walter Reed Project, Kampala, Uganda; 3 Walter Reed Project, Kericho, Kenya; 4 Walter Reed Project - Tanzania, Mbeya, United Republic of Tanzania; 5 Walter Reed Army Institute of Research, Silver Spring, MD, US Background: Cognitive impairment remains a frequent complication of HIV despite access to antiretroviral therapy. Few data exist regarding risk factors in resource-limited settings. Methods: The African Cohort Study (AFRICOS) aims to longitudinally assess the impact of clinical practices, biological factors and socio-behavioral issues on HIV infection and disease progression in an African context. All enrollees undergo the International HIV Dementia scale (IHDS), an auditory verbal learning and delayed recall task (AVLT-DR), the grooved pegboard (GP) test in both hands, the Trail Making A test and an action fluency task. We examined factors that correlate to neuropsychological testing performance including CD4 count, nadir CD4 count, plasma HIV RNA, age, educational attainment, infectious and non-infectious comorbidities among other clinical variables from data captured in Kenya, Uganda, and Tanzania. Results: 779 HIV-infected and 149 HIV-uninfected subjects were evaluated. The HIV-infected group was 58% female, had a mean (SD) age of 41 (10) and 63% had 6 or fewer years of education. 73%were taking combination antiretroviral therapy at the time of testing. Mean (SD, range) IHDS was 8.7 (1.7, 1-12) for the HIV infected group compared to 9.0 (1.7, 3-12) for the HIV-uninfected controls (p = 0.022). HIV status, age, and educational attainment were all associated with performance on all tests (p’s<0.02). CD4 nadir count was associated with AVLT-DR (p=0.003) and at trend level for GP dominant hand (p=0.096). We found no association between cognitive performance and the number of infectious nor non-infectious comorbidities. Conclusions: This study investigated correlates to neuropsychological performance in over 900 study participants from East Africa. Cognitive impairment is associated with HIV-infection, age and educational attainment. Similar to findings from resource-rich regions, CD4 nadir count was associated with performance on two tests. Unlike resource-rich areas, where cognition is increasingly associated with non-HIV factors, the number of comorbidities did not correlate to cognitive performance, a factor that may be due to the relative younger age of the group. 2:30 pm– 4:00 pm HAND Genetics 460 Mitochondrial DNA Haplogroups and CSF Neuroinflammation in the CHARTER Cohort Todd Hulgan 4 ; David Samuels 4 ; Ronald J. Ellis 1 ;William Bush 2 ; Scott Letendre 1 ; Donald Franklin 1 ; Igor Grant 1 ; Asha R. Kallianpur 3 CHARTER Group 1 University of California San Diego, San Diego, CA, US; 2 Case Western Reserve University, Cleveland, OH, US; 3 Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH, US; 4 Vanderbilt University, Nashville, TN, US Background: Neurocognitive impairment (NCI) remains an important complication in the combination antiretroviral therapy (CART) era, and is associated with neuroinflammation in cerebrospinal fluid (CSF). Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-uninfected populations, and HIV- and CART-associated outcomes in HIV-infected persons. We hypothesized that mtDNA haplogroups would be associated with neuroinflammation in HIV-infected adults. Methods: CHARTER is a U.S.-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants without confounding neurocognitive comorbidities and who consented to DNA collection underwent mtDNA sequencing fromwhole blood. A subset also underwent lumbar puncture. IL-6, IL-8, TNF- α (high-sensitivity), VEGF, IP-10, and novel soluble biomarkers of brain iron homeostasis, antioxidant defense, and inflammation- ceruloplasmin (CP) and haploglobin (HP)- were measured in CSF by immunoassay. Haplogroups were assigned using HaploGrep. Multivariable regression of mtDNA haplogroups and log-transformed CSF biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African [AA], or admixed Hispanic ancestry [HA]), and adjusted for age, sex, CART, detectable CSF HIV RNA, and CD4 nadir. Results: Haplogroups could be assigned in 385 subjects with evaluable CSF (45% EA, 44% AA, 11% HA, 20% female, median age 43 years, CD4 nadir 175 cells/mm 3 , 74% on CART). Statistically significant adjusted haplogroup-biomarker associations included higher IP-10 in HA subjects with haplogroup B (N=12; p=0.03) and higher CP with haplogroups L1 (N=32) and L2 (N=52) in AA subjects (p=0.02 and 0.01, respectively). Among EA subjects, mtDNA haplogroups were not significantly associated with these CSF biomarkers. Several additional associations of IL-6, IL-8, IP-10, and TNF- α with age, sex, CD4 nadir, CSF HIV detectability, and CART were observed independent of mtDNA haplogroup. Conclusions: We observed associations between mtDNA haplogroups and CSF IP-10 and CP in HA and AA CHARTER subjects, respectively, independent of other potential confounders. These preliminary results suggest novel mechanisms of neuroinflammation and perhaps NCI that merit further exploration. 461 Iron-Regulatory Genes Are AssociatedWith Neuroimaging Traits in HIV Infection Tricia A.Thornton-Wells 2 ; Christine Fennema-Notestine 3 ;Todd Hulgan 4 ; Scott Letendre 5 ; Ronald J. Ellis 6 ; Asha R. Kallianpur 1 ; for the CHARTER Group 7 1 Cleveland Clinic/Lerner Research Institute, Cleveland, OH, US; 2 Vanderbilt University School of Medicine, Nashville, TN, US; 3 University of California San Diego, San Diego, CA, US; 4 Vanderbilt University School of Medicine, Nashville, TN, US; 5 University of California San Diego, San Diego, CA, US; 6 University of California San Diego, San Diego, CA, US; 7 University of California San Diego (UCSD), San Diego, CA, US Background: HIV-Associated Neurocognitive Disorders (HAND) remain highly prevalent, despite viral suppression with combination antiretroviral therapy. Structural and metabolic changes in the brain may occur early in HIV-infection and represent important endophenotypes of HAND. Since brain iron dysregulation is a common feature of neurodegenerative disorders and iron is linked to immune regulation, we hypothesized that iron-regulatory-gene variants contribute to neuroimaging traits in HIV-infected persons with or without HAND. Methods: We genotyped 250 SNPs in 12 iron-related genes and evaluated their associations with magnetic resonance (MR) imaging traits in 243 subjects with neuroimaging data from CHARTER, a multicenter, observational neuro-HIV study. Structural MR imaging measurements of gray matter (GM) and white matter (WM) volume and MR spectroscopy measurements of brain metabolites were made in 21 regions of interest (ROI); T2* images were unavailable. Multivariable regression models of log-transformed neuroimaging THURSDAY, FEBRUARY 26, 2015 Session P-G4 Poster Session Poster Hall

Poster Abstracts

316

CROI 2015