CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: Each triplicate revealed 2,000-5,000 MFs and these were down selected based on a FC of 1.5 between IRIS and non-IRIS at each time point with a significance of p<0.05. The greatest difference between the IRIS and non-IRIS samples was observed with the IRIS window time point and included 59 MFs for all replicates analyzed. Four metabolomics databases (METLIN, HMDB, MTB LIPID MAPS and LIPID MAPS) were searched to provide a putative identification of the MFs. MF presumed to be small peptides and lipids (triglycerides, glycosphingolipids, vitamin D metabolites) dominated the signature. Some of the putative lipids are in well-known inflammatory pathways. Each significant MF was manually crossed checked against our in-laboratory Mtb lipid database and no matches were found, leading us to believe that the lipid molecules identified are of host origin. Targeted LC-MS analyses are currently underway to confirm identities and further assess changes in lipid metabolism of IRIS subjects. Conclusions: These studies provide evidence that a biosignature based on metabolites can separate IRIS from non-IRIS early in the course of disease and may be able to predict those at risk for IRIS. Lipid species appear in our discriminatory signature. Efforts are ongoing to formally identify each of the significant MF we discovered. Ultimately we aim to confirm and validate our findings using samples collected in prospective trials or sites studying HIV/Mtb co-infected individuals who develop IRIS. 310 Associations Between Plasma Cytokine and Microbial Translocation Biomarkers and IRIS Margaret A. Fischl 2 ; Linda J. Harrison 1 ;Varghese George 2 ; Margaret Roach 2 ; Xiao-Dong Li 3 ; David Asmuth 3 ; PabloTebas 4 ; CamlinTierney 1 ; Catherine Godfrey 5 ; Savita Pahwa 2 1 Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA, US; 2 University of Miami Miller School of Medicine, Miami, FL, US; 3 University of California Davis, Sacramento, CA, US; 4 University of Pennsylvania, Philadelphia, PA, US; 5 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US Background: IRIS is a pathogen-specific inflammatory response associated with ART initiation. We conducted a nested case-cohort study among subjects in a large prospective randomized longitudinal clinical trial (A5202) in the USA and investigated 18 plasma biomarkers of inflammation and microbial translocation for their association with risk of IRIS. Methods: ACTG A5202 compared ABC/3TC or TDF/FTC combined with ATV/r or EFV for first-line HIV treatment. IRIS events were defined using ACTG criteria; unmasking and paradoxical events were included. 51 of 1452 subjects with baseline CD4<350 cells/mm 3 developed IRIS (3.9 cases/100 person years). We analyzed 100 randomly selected subjects (94 non-IRIS, 6 IRIS, stratified by pre-enrollment CD4 ≤ 200 cells/mm 3 ) and 45 additional IRIS cases. Plasma samples at baseline (n=141), an early time-point (~week 4, n=138) and week 48 (n=136) were tested for tumor necrosis factor (TNF), sTNF receptor I, sTNF receptor II, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), interferon (IFN) gamma, IFN alpha 2, IFN gamma inducible protein 10 (IP-10), IL-1 beta, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17, sCD14 (ELISA, Luminex or electrochemiluminescence), lipopolysaccharide (LPS, Limulus amebocyte lysate assay) and 16s ribosomal (r) DNA(PCR). Cox models, stratified by pre-enrollment CD4 and weighted for the case-cohort design, evaluated associations between baseline biomarkers and time to first IRIS event. Logistic models evaluated associations between biomarker levels at week 4 and 48 and IRIS. Results: The 145 subjects included 79%male (34%with AIDS history), median age 39 years, baseline HIV-1 RNA 4.8 (IQR 4.6-5.4) log 10 c/ml, CD4 84 (30-184) cells/mm 3 . At baseline, higher IP-10, LPS, sCD14, 16s rDNA and IFN alpha 2 were associated with greater risk of IRIS (Table). There was a significant (p=0.012) non-linear relationship between MCP-1 and IRIS. These results were supported by adjusted models; other biomarkers had p ≥ 0.15. Most biomarkers (TNF, sTNFRII, G-CSF, MCP-1, IP-10, IL-8, IL-10, IFN alpha 2, LPS, sCD14) decreased after ART initiation. IP-10 and LPS at week 4 were still associated with IRIS. At week 48, this association only remained for IP-10.

Poster Abstracts

Conclusions: Enhanced systemic inflammatory response presumably through persistent monocyte activation and bacterial translocation in immunosuppressed patients appear important in the pathogenesis of IRIS and may be useful to predict risk for IRIS 311 Potential Role of IL-1 and IL-10 Pathways in IRIS Pathogenesis Ainhoa Perez-Diez; Elizabeth Richards ; Stig Jensen; Eleanor M.Wilson;Virginia Sheikh; Maura M. Manion; Bruno Andrade;Timothy Myers; Irini Sereti National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD, US Background: Inflammation and immune activation play a central role in HIV pathogenesis. An exuberant inflammatory response, termed Immune Reconstitution Inflammatory Syndrome (IRIS), occurs in a subset of patients shortly after starting antiretroviral therapy (ART), and is more common in those with severe lymphopenia and underlying opportunistic infections. The pathogenesis and etiology of IRIS remain unclear. Microarray analysis of patient samples prior to ART initiation could allow the unbiased study of genes and molecular signatures in patients before they develop clinical manifestations of IRIS and help us understand the molecular pathways triggering the syndrome. Methods: Gene expression profiles were measured by microarray analysis of peripheral mononuclear cells (PMC) obtained before ART from 143 HIV+ patients. Data were initially analyzed by the non-supervised method Principal Component Analysis (PCA), followed by supervised methods using Ingenuity Pathway Analysis (IPA). To detect which molecular

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CROI 2015