CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

342 SYSTEMIC INFLAMMATORY AND IMMUNE BIOMARKERS IN NEUROCOGNITIVE CHANGE WITH INITIAL ART Kevin Robertson 1 , Sachiko Miyahara 2 , Alan Landay 3 , Todd Brown 4 , Carl Fichtenbaum 5 , Joseph J. Eron 6 , Athe Tsibris 7 , Babafemi Taiwo 8 , for the ACTG 5303Team 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 Harvard Univ, Boston, MA, USA, 3 Rush Univ, Chicago, IL, USA, 4 The Johns Hopkins Univ, Baltimore, MD, USA, 5 Univ of Cincinnati, Cincinnati, OH, USA, 6 Massachusetts General Hosp, Cambridge, MA, USA, 7 Northwestern Univ, Chicago, IL, USA Background: HIV associated neurocognitive impairment remains problematic despite suppressive antiretroviral therapy (ART). Understanding the mechanisms and biomarkers of this impairment is necessary for targeted intervention and clinical trials design. We investigated the association between neurocognition and systemic immune, inflammatory and coagulation biomarkers in ACTG A5303. Methods: ACTG A5303 enrolled ART naïve participants with CCR5 tropic HIV-1 and viral load (VL) >1000 copies/mL in the US, who were randomized to maraviroc or tenofovir disoproxil fumarate plus darunavir/ritonavir + emtricitabine. 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. Thirty-one systemic immune, inflammatory and coagulation biomarkers were assessed at baseline and 48 weeks. Analyses were as-treated and included only participants who remained on randomized study arms through week 48. Spearman correlations evaluated associations between NP scores and biomarkers. Adjustment for multiple testing was not applied to this exploratory analysis. Results: Of the 230 participants, 220 individuals with both baseline and week 48 NP and biomarker data were included in this analysis. Most (91%) were male; median age was 33 yrs, 44%White, 31% Black, 22% Hispanic; >12 years education 70%; median VL was 4.5 log10 c/mL (IQR:4.5-5.0) and CD4 count was 389 (IQR:293-508) cells/mm3. At baseline (pre- ART), there were weak correlations between NP total z score and IP10 (r=-0.19), CD38+/HLA-DR+(CD4+)% (r=-0.22), and CD38+/HLA-DR+(CD8+)% (r=-0.25). At week 48, weak total z score and biomarker correlations were found for CD14++CD16-(classical monocytes)% (r=0.25), and CD14+CD16++ (non-classical monocytes)% (r=-0.26) as expected. All other biomarkers showed even weaker or no correlation with NP at baseline and week 48. We found no significant association between the changes in NP and changes in immune or inflammatory biomarkers from baseline to week 48. Conclusion: We found no significant association between changes in systemic immune and inflammation biomarkers during ART and neurocognitive functioning. This suggests that systemic responses may poorly reflect changes within the CNS. The correlations between NP and monocyte subsets after ART initiation, though modest, are consistent with a role for monocytes in HAND persistence during ART. 343 IMPACT OF ADVANCING AGE ON COGNITION IN HIV+ PERSONS ON A FIRST SUPPRESSIVE REGIMEN Hamza Coban 1 , Kevin Robertson 2 , Kunling Wu 3 , Ronald Bosch 3 , Ronald J. Ellis 4 1 Univ of California San Diego, La Jolla, CA, USA, 2 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 3 Harvard Univ, Boston, MA, USA, 4 Univ of California, San Diego, CA, USA Background: We evaluated the relationship of advancing age to neurocognitive (NC) performance over time in a large cohort of individuals who had initiated their first virologically suppressive antiretroviral therapy (ART) regimen. Methods: This analysis included ART-naïve individuals from 7 randomized ART parent trials of the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort. All underwent annual NC testing with the ACTG NeuroScreen. Only assessments done after the participants had been on ART for at least 2 years were included in this analysis. Overall performance, calculated by comparison to normative data from HIV negative individuals, was summarized using mean z-scores across the 4 tests (NPZ-4). Impairment was defined as ≤ -2.0 SD on one test or ≤ -1.0 SD on two tests. Uni- and multi-variable repeated measures regression models evaluated predictors of NC performance. Predictors evaluated included entry demographics, smoking, injection drug use (IDU), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 and plasma viral load (PVL) and as well as time-updated PVL and CD4. Variables significant at p≤0.10 were eligible to enter the multivariable models. Results: The cohort comprised 3,313 individuals with a median age at parent entry of 38 [IQR 31, 45; 12% over age 50], 36% Black, non-Hispanic; 22% Hispanic; CD4 nadir median 221 [IQR 82, 324]. Median duration of NC follow-up was 3.4 years (range 0-6.4). Considering the cohort as a whole, NC performance improved year on year such that 23%were classified as impaired at the first analyzed visit compared to only 13% in the last analyzed visit. After adjusting for the expected effects of age using norms from HIV–negative individuals, the odds of NCI impairment at a visit among HIV+ participants increased for each decade of advancing age (OR 1.18 [1.1,1.25]). Virologic suppression, which was maintained at 91% of follow-up visits, was not related to NC worsening. Conclusion: Despite continued virologic suppression and overall NC improvement in the cohort as a whole, older individuals tended to have worse NC performance, after consideration of concurrent predictors, than younger individuals. Future studies should evaluate potential mediators of the adverse effects of age on NC trajectories, such as inflammation and vascular risk factors. 344 WITHDRAWN 345 IMMUNE MARKERS OF CRYPTOCOCCAL REACTIVATION IN HIV INFECTION Admire Hlupeni 1 , Kathryn F. Boyd 2 , Azure T. Makadzange 3 , Chiratidzo E. Ndhlovu 1 1 Univ of Zimbabwe, Harare, Zimbabwe, 2 Infectious Disease Rsr Lab, Harare, Zimbabwe, 3 Massachusetts General Hosp, Cambridge, MA, USA Background: Cryptococcal infection establishes latent stage that can be reactivated in the setting of advanced HIV infection particularly in individuals with CD4+ T cells ≤100 cells/μl. Reactivation of subclinical infection can be detected by a positive serum cryptococcal antigen (sCrAg) prior to disease dissemination and cryptococcal meningitis (CM). Host factors governing reactivation remain unclear. In animal models, innate, Th17 and Th1immune responses are associated with disease containment. Human studies have focused on patients with disseminated cryptococcal disease. Methods: We determined the factors associated with reactivation by studying a cohort in Zimbabwe of sCrAg+ individuals prior to the onset of symptomatic meningitis. We analyzed serum from 43 sCrAg+ and 23 sCrAg- individuals; paired CSF was available for 38 sCrAg+ participants, 7 of whomwere also CSF CrAg+. A panel of 26 cytokines (Flt-3L, G-CSF,GM-CSF, IL-10,IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17α, IL-1α,IL-1β , IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, INF- α 2, INF-γ, IP-10, MCP-1, MIP-1α, MIP-1β, sCD40L,TNF-α,TNF-β) was measured (in pg/ml) using multiplexed Luminex sandwich immunoassays. Results: Median age and CD4 count were 38 years (IQR: 33-42) and 17 cells/mm3 (IQR: 10-32) respectively; most participants were male (66.7%). Median serum IL-17α (1.2 (0.64- 3.3) vs 0.64 (0.64-1.8)pg/ml, p=0.032) and MIP-1β (32.6 (24.4-99.4) vs 18.7(2.5-47.1) pg/ml, p=0.02) levels were significantly higher in sCrAg- compared with CrAg+. Serum IP10 levels were higher in the CrAg+ (2041 (1510.6-2666.6)pg/ml) than in the CrAg- (1207 (757.7-1797.6pg/mL), p=0.028). There were no significant differences in the expression of the other cytokines. A model comprising of serum IP-10, IL-17α, G-CSF, sCD40L and IL-10 had a 97% predictive accuracy of an individual’s serum CrAg status (95.3% PPV and 100% NPV). There was no difference in serum and CSF cytokine expression levels between those who were CSF CrAg+ and those that were CSFCrAg- Conclusion: Serum IL-17α, MIP-1β and IP10 are important regulators of cryotococcal disease reactivation in patients with advanced HIV infection. IFNγ was not associated with reactivation, however IP10 which is produced in response to IFNγ and is associated with poor outcomes in HIV infection, was associated with disease reactivation. A model of serum IP-10, IL-17α, G-CSF, sCD40L and IL-10 predicts reactivation and suggests important immunomodulatory roles of these cytokines in cryptococcal reactivation.

Poster and Themed Discussion Abstracts

CROI 2017 135