CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Conclusion: No change in neuroinflammatory markers were observed. Whilst a learning effect cannot be entirely excluded, in this small study the addition of 24 weeks of MVC 150mg to stable DRV/r monotherapy showed a tendency to improvement in overall NC function overall at w36, and a significant improvement in executive function. The mechanism of this improvement should be further evaluated. 383 CSF LEVELS OF THE GLIAL MARKER YKL-40 STRONGLY ASSOCIATED WITH NEURONAL INJURY IN HIV Linn Hermansson 1 , Markus Axelsson 1 , Kaj Blennow 2 , Dietmar Fuchs 3 , Lars Hagberg 1 , Jan Lycke 1 , Henrik Zetterberg 1 , Magnus Gisslén 1 1 Sahlgrenska Academy at the Univ of Gothenburg, Gothenburg, Sweden, 2 Sahlgrenska Univ Hosp, Gothenburg, Sweden, 3 Innsbruck Med Univ, Innsbruck, Austria Background: CNS inflammation is a nearly universal component of HIV-1 infection present throughout the entire infectious course. The objective of this study was to characterize cerebrospinal fluid (CSF) YKL-40, a biomarker that reflects activation of astroglial and microglial cells, in chronic HIV infection, with and without antiretroviral treatment (ART). Methods: YKL-40, neopterin, and neurofilament light protein (NFL) were analyzed with ELISA in archived CSF samples from 120 HIV-infected (85 untreated neurological asymptomatic (NA) patients; 7 with HIV associated dementia (HAD); and 28 on effective ART), and 39 HIV-negative controls. Results: YKL-40 was significantly higher in HAD compared to all other groups, but was also higher in untreated NA patients with CD4 <350 compared to HIV-negative controls. NA patients with CD4 >350 and persons on ART didn’t have significantly different CSF YKL-40 levels compared to controls. Significant correlations were found between CSF YKL-40 and age (r=0.38, p<0.001), CD4 (r=-0.36, p<0.001), plasma HIV-RNA (r=0.35, p<0.001), CSF HIV-RNA (r=0.35, p<0.001), CSF neopterin (r=0.40, p<0.001), albumin ratio (r=0.44, p<0.001), and CSF NFL (r=0.71, p<0.001). Age, CD4, albumin ratio, and CSF HIV RNA were found as independent predictors of CSF YKL-40 concentrations in a multivariable analysis. CSF YKL-40 was shown to be a strong independent predictor of CSF NFL in a multivariable analysis, together with age, CSF neopterin, and CD4 cell count. Conclusion: This study suggests that CSF YKL-40 could be a valuable marker in understanding HIV neuropathogenesis. The strong correlation between CSF YKL-40 and NFL give support to a pathogenetic association between glial activation and neuronal injury and suggest the utility of further exploring the prognostic value of YKL-40. 384 EXTENSIVE EFAVIRENZ METABOLISM IS ASSOCIATED WITH GREATER CNS TOXICITY Marijana Vujkovic 1 , Scarlett Bellamy 2 , Athena Zuppa 1 , Marc Gastonguay 3 , Xiaoyan Han 4 , Mosepele Mosepele 5 , Gregory Bisson 4 , Richard Aplenc 1 , Robert Gross 4 1 Children’s Hosp of Philadelphia, Philadelphia, PA, USA, 2 Drexel Univ, Philadelphia, PA, USA, 3 Metrum Rsr Group, Tariffville, CT, USA, 4 Univ of Pennsylvania, Philadelphia, PA, USA, 5 Univ of Botswana, Gaborone, Botswana Background: Efavirenz causes central nervous system adverse effects (CNS AEs) including sleep disturbance, somnolence, vivid dreams and others. The relation between efavirenz clearance and CNS AEs has been unclear, particularly when stratified by race. P450 (CYP) isoenzyme 2B6 G516T confers slower metabolism and is more common with African origin. We hypothesized that this allele and additional CYP polymorphisms that affect efavirenz clearance mediate CNS AEs. Methods: We included 842 HIV infected adults initiating efavirenz + 2 nucleoside analog reverse transcriptase inhibitors in a cohort study in Botswana. DNA was genotyped for 21 variants in CYP 2B6, 2A6, 3A4, and 3A5 genes and mid-dose EFV plasma samples were collected at 1 month of therapy. AEs were measured using 21 CNS symptoms in the ACTG Subject Experience Questionnaire. We used a one-compartment population PK model with nonlinear mixed effect modeling in NONMEM 7 to estimate EFV clearance, including the fixed covariates of allometrically scaled weight, G516T genotype, and visit number. SNPs that resulted in the greatest statistically significant decrease in the minimum objective function value (MOFV) were regarded as either extensive or slowmetabolizers. Associations between metabolizer groups and CNS AEs were evaluated using negative binomials in a generalized linear regression model including the covariates: plasma EFV concentration, CYP2B6 G516T genotype, age, gender, alcohol intake, baseline CD4 count and viral load. Results: The initial covariate model showed a MOFV of 2075. Two SNPs showed a reduced apparent oral EFV clearance: rs28399499 (8.0, 4.7, and 1.4 L/hr/70kg for TT, CT, CC, MOFV=1768) and rs28399433 (7.6, 5.9, and 4.9 L/hr/70kg for TT, GT, GG, MOFV=2015). Four SNPs showed extensive apparent clearance: rs2279345 (6.5, 8.0, and 8.4 L/hr/70kg for TT, CT, CC, MOFV=1995), rs4803417 (6.8, 8.3, and 9.4 L/hr/70kg for AA, AC, CC, MOFV=2015), rs4802101 (7.3 and, 8.6 L/hr/70kg for AA, AG, MOFV=2037), and rs61663607 (7.2, 7.2, and 8.7 L/hr/70kg for TT, CT, CC, MOFV=2021). Faster efavirenz clearance was associated with greater reported CNS AEs (β=0.42, p=0.01, see Figure). Conclusion: In a model including multiple fast and slow clearance polymorphisms, faster clearance was associated with more CNS AEs. These findings implicate metabolites rather than parent drug as the cause of efavirenz-related CNS AEs. Assays for extensive CYP polymorphisms may permit avoidance of EFV in HIV-infected Africans at high risk of CNS AEs.

Poster and Themed Discussion Abstracts

CROI 2017 154