CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

1 University of California San Diego, La Jolla, CA, USA, 2 Harvard University, Boston, MA, USA, 3 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 4 Tulane University, Metairie, LA, USA Background: HIV associated neurocognitive impairment (NCI) is a common complication of perinatal HIV infection and is associated with elevated markers of inflammation. Here we identified host genetic variants associated with NCI in HIV-infected children (2 mo-18 yrs). Methods: Whole exome sequencing was performed on 195 HIV-infected children with NCI (standardized global cognitive score for age (CSA) <70) and 211 infected controls matched for age, CD4+ count and viral load without NCI evaluated prior to the start of ART (P152/P300-Discovery Cohort [DC], mean age: 2.7 yrs). SNPs identified in DC were evaluated in 2 validation cohorts (VC): PHACS AMP (CSA <70: n=61; >70: n=306; mean age: 11.6 yrs): a contemporary longitudinal study of perinatal HIV-infected children; and P338/P377 (CSA <70: n=54; >70: n=303, mean age: 6.8 yrs) consisting of children stable on NRTI therapy prior to treatment with either ritonavir (P338) or nevirapine, nelfinavir or ritonavir (P377). Logistic regression was used to estimate adjusted odds ratios (OR). The combined, across study, OR estimate was computed using inverse variance weights. P-values <.05 were considered to be statistically significant. Results: 22 SNPs with >5 subjects/SNP in 19 genes reaching p <0.001 and OR >1.5 for each comparison of cognitively impaired group to controls with >70, >85 and >100 CSA were identified in the DC. The 22 SNPs were evaluated by PCR in the PHACS Adolescent Master Protocol cohort and identified 3 SNPs, CCRL2 (rs3204849), FAM134B [RETREG1] (rs61733811) and YWHAH [14-3-3 proteins] (rs73884247) comparing CSA 70 with similar 95% confidence interval (CI) for the OR. These 3 SNPs were further evaluated in a second VC from PACTG 338/377. Only the OR for rs73884247 was in the same direction (OR >1.0). However, the overall 95% CI for the ORs excluded the null hypothesis, indicating that the overall difference is statistically significant (rs3240849: p<.0001, rs6173381: p<.0001, rs73884247: P<.001; Figure). Conclusion: Using whole exome sequencing and two VCs, we have identified three genetic variants that are associated with NCI in HIV-infected children. Since YWHAH and CCRL2 binding to chemerin both affect mTORC1 phosphorylation and FAM134B plays a role in autophagosome formation, a potential common mechanism for these three genetic variants is the modulation of autophagy leading to altered inflammation affecting neurocognitive function.

822 SYSTEMIC INFLAMMATION AND STRUCTURAL BRAIN CHANGES IN PERINATALLY HIV+ ADOLESCENTS Jackie Hoare , Landon Myer, Sarah Heany, JP Fouche, Nicole Phillips, Heather Zar, Dan Stein University of Cape Town, Cape Town, South Africa Background: Neurological impairments despite ART are well documented in perinatally-infected HIV+ adolescents (PHIV) but the mechanisms that drive this are not well defined. Systemic inflammation may be one mechanism but this has not been investigated in adolescence when the brain is undergoing rapid development. Methods: Baseline data were drawn from the Cape Town Adolescent Antiretroviral Cohort (CTAAC). PHIV on ART >6m at public sector facilities completed a comprehensive neurocognitive test battery assessing function in 10 cognitive domains. Diffusion tensor imaging and structural brain magnetic resonance imaging (MRI) was done to determine fractional anisotropy (FA), mean diffusivity (MD), axial diffusion (AD), radial diffusion (RD) gray and white matter volumes, cortical thickness and cortical surface area. In analysis we examined how neurocognitive and neurostructural measures were associated with concurrently measured markers of systemic inflammation including hs-CRP and fasting low density lipoprotein-cholesterol (LDL-C). Results: Overall 204 PHIV ages 9-12 years (mean CD4 cell count 953 cells/µL and 85.3% VL<50 copies/mL) and 44 age-matched HIV- controls completed all assessments. PHIV had higher hs-CRP (p<0.001) and LDL (p=0.06) vs controls. Among PHIV, hs-CRP negatively correlated with multiple neurocognitive measures including general intelligence (p=0.005), attention (p=0.015), working memory (p=0.003), visual space acuity (p=0.005), processing speed (p<0.001), and executive function (p=0.002); LDL-C negatively correlated with Language (p=0.048); however none of these correlations were apparent among controls. In measurements of the fornix and internal capsule FA, AD, MD and RD all increased with higher hs-CRP values (p<0.005 for all associations). Higher MD and RD are suggestive of inflammation and myelin loss. There were no associations in PHIV or controls between hs-CRP and global brain measures (total grey matter, total white matter, mean cortical thickness), but whole brain mean cortical thickness increased with higher levels of LDL-C in PHIV (p=0.027). Conclusion: Markers of systemic inflammation appear associated with both neurocognitive impairment and structural brain changes in PHIV. While further investigation including long-term follow-up is required, this provides novel evidence that inflammatory mechanisms may drive persistent neurological impairment in PHIV. 823 GENOMICS LINKS AUTOPHAGY WITH NEUROCOGNITIVE IMPAIRMENT IN HIV-INFECTED CHILDREN Stephen A. Spector 1 , Sean S. Brummel 2 , Kumud K. Singh 3 , Jihoon Kim 1 , Kelly Frazer 1 , Sharon Nichols 1 , Olivier Harismendy 1 , George R. Seage 2 , Paige L. Williams 2 , Russell B. Van Dyke 4 , Rodney Trout 1

Poster Abstracts

824 HIGH PRESCRIPTION ERROR RATES AMONG CHILDREN ON ANTIRETROVIRAL THERAPY IN KENYA

Irene Mukui 1 , Samuel M. Mwalili 2 , Barbra A. Richardson 3 , Elizabeth A. Bukusi 4 , Carey Farquhar 3

CROI 2019 320