CROI 2016 Abstract eBook

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Poster Abstracts

peripheral blood mononuclear cells (PBMC) by flow cytometry, b) soluble markers of immune activation (CD14, CRP, D-dimer, IL-6, CD163) in plasma by ELISA, and c) HIV RNA in rectal mucosa biopsies by in situ hybridization (confirmed by reverse transcriptase-ddPCR). Differences between BL and EoT were tested, using non-parametric Wilcoxon Sign-Rank test or paired t-tests, depending on data distribution. A p<0.05 was considered significant. Results: 17/20 subjects completed the treatment; 3 subjects were withdrawn prematurely due to adverse event (AEs; neutropenia). 9/17 subjects had VL>50 copies/ml during ART interruption, returning to undetectable upon ART re-initiation. Coupled (BL-EoT) rectal biopsies were available for 15/17 subjects with 7 of them having detectable tissue in situ HIV RNA at BL. Of these, 7/7 had a decrease in tissue HIV RNA at EoT, with a complete loss of detectable tissue HIV RNA in 5/7. 1 subject had detectable tissue HIV RNA at EoT, but not at BL. We observed a decrease in CD4 + T cell count and an increase in CD4 + and CD8 + T cell activation (CD38, HLA-DR, PD1) and Tetherin expression between BL and EoT. Higher frequencies of CD56 bright and lower of CD56 dim CD16 + NKs at EoT were also found, as well as an increase in CD38 and NKG2A in both NK subsets. In the myeloid compartment, we noted an increase in CD169 and Tetherin, and in plasma levels of CD163. No changes in plasma CD14, CRP, D-dimer, or IL-6 were found. Conclusions: 20 weeks of combined Peg-IFN-a2b+ART, including a 4-week ART interruption, result in a decrease in tissue HIV RNA and an increase in peripheral innate and adaptive immune activation. 291 Background: Low CD4/CD8 ratios may increase risk of clinical events, and earlier antiretroviral therapy (ART) may lead to a higher likelihood of CD4/CD8 normalization. We estimated time to CD4/CD8 normalization following ART initiation and risk of mortality and serious clinical events among acutely and chronically infected patients. Methods: Patients who achieved HIV RNA suppression within 1 year of ART initiation between 2000 and 2014, were included from the UNC CFAR HIV Clinical Cohort Study (chronic HIV infection, CHI) and the Acute HIV Infection Study (acute HIV infection, AHI). Normalization was defined as a ratio ≥1. Kaplan-Meier and multivariable Cox proportional hazards methods were used to model time from ART initiation to normalization and outcomes of interest, adjusting for baseline covariates. Results: AHI patients (n=102) were younger and more likely men than CHI patients (n=545), (median 28 vs. 38 years old; 89% vs. 73%; both p<0.001). At ART initiation AHI versus CHI patients had higher CD4 (median 489 vs. 203 cells/mm3; p<0.001) and were more likely to have a normal CD4/CD8 ratio, 14% and 2%, respectively. 57% and 14% of AHI and CHI patients had normal ratios at 1 year of suppressive ART, respectively. Median times to normalization were 6, 16, 43, 51 and >125 months among AHI and CHI patients with ART initiation CD4>500, 350, 200-350 and <200 cells/mm3, respectively (log-rank p<0.001). In multivariable analyses AHI patients had shorter time to normalization (Hazard Ratio [HR]=2.7, 95% Confidence Interval [CI] 2.0-3.7), as did older patients and those with a higher CD4 (HR=1.14, 1.0-1.3 per 10 years; HR=1.3, 1.3-1.4 per 100 CD4). Among patients initiating ART with CD4>500, AHI patients also had shorter time to normalization with adjusted HR of 1.9 (1.2, 3.1). During 4,097 person-years of follow-up, 92 patients died. Having a normalized CD4/CD8 ratio at 1 year post-ART initiation had no apparent effect on all-cause mortality or a composite endpoint of serious non-AIDS clinical events and mortality (HR=0.8, 0.4-1.8; HR=1.1, 0.6-2.0; respectively). Conclusions: CD4/CD8 normalization occurred earlier among AHI versus CHI patients but early normalization did not appear to predict mortality and serious non-AIDS events using a stringent criterion for normalization. The effect of longitudinal CD4/CD8 ratios on serious clinical events among patients on suppressive ART is important to evaluate given proposed hypotheses of an association with immune activation and immunosenescence. 292 Acute HIV Treatment Reverses CD8 T Cell Activation, Exhaustion, and Apoptosis Jessica Eagar 1 ; Sarah D. Sterrett 1 ; Nilesh Amatya 2 ; Anju Bansal 1 ; Steffanie Sabbaj 3 ; Katharine J. Bar 4 ; Sonya L. Heath 1 1 Univ of Alabama at Birmingham, Birmingham, AL, USA; 2 Univ of Pittsburgh, Pittsburgh, PA, USA; 3 Univ of Alabama at Birmingham, Birmingham, AL, USA; 4 Univ of Pennsylvania, Philadelphia, PA, USA Background: Despite viral suppression with cART, persistent inflammation contributes to pathogenesis and morbidity. We hypothesized that treatment during acute HIV infection (AHI) with an integrase inhibitor based regimen would decrease cellular activation, exhaustion, and apoptosis compared with subjects treated in chronic infection. Methods: Subjects identified in AHI (n= 18, Fiebig stages I-IV), were treated with tenofovir/emtricitabine and either raltegravir (RAL) or efavirenz (EFV). Matched chronically HIV infected subjects (CHI) (n=25) served as controls. Using flow cytometry, we measured surface expression of markers of activation (CD38), exhaustion (PD-1, CD160, CD244), senescence (CD57), pro-survival (Bcl-2) and apoptosis (cleaved-caspase-3) on CD8 T cells pre- and post-treatment. Comparisons were made within groups (Wilcoxon rank) and between groups (Mann-Whitney test), p< 0.05 denoted by *. Results: Treatment in both AHI and CHI cohorts significantly reduced the frequency of activated CD38+ CD8 T cells (acute pre ART and virally suppressed (VS): 28% vs 6.3%,*, chronic 24% vs 17%,*), and, VS AHI had lower frequency compared with VS CHI (6.3% vs 17%,*). Treatment also reduced some markers of exhaustion, reducing the frequency of PD-1hi CD8 T cells in both groups (AHI 5.6% vs 2.3%,*, CHI 11% vs 7.1%,*), with greater reduction in VS AHI (VS AHI 2.3% vs VS CHI 7.1%,*). Treatment in both AHI and CHI reduced the frequency of apoptotic CD8+ T cells (CC-3hi/Bcl-2lo) (AHI 8.7% vs 2.9%,*,CHI 8.3% vs 5.2%,*), with greater reduction in VS AHI (VS AHI 2.9% vs VS CHI 5.2%,*). Despite early treatment, viral suppression in AHI did not impact expression of CD160, CD57, or CD244. Enumeration of memory markers (naïve, central (CM) and effector memory (EM)) demonstrated that AHI treatment resulted in fewer CD8 T EM populations when compared to CHI (4.9% vs 32%,*), but did not impact naïve or CM. There was a trend to faster time to undetectable VL in the RAL vs EFV arm. No differences were observed in immune parameters between RAL vs EFV groups. Treatment in AHI resulted in more subjects achieving normal CD4% (AHI 85% vs CHI 22%,*) and CD4/CD8 ratios of >1 (AHI 95% vs CHI 60%,*). Conclusions: Treatment during acute HIV reverses some measures of immune inflammation, including CD8 T cell activation (CD38), exhaustion (PD-1), and apoptosis (CC-3hi/ Bcl-2lo) and results in more robust immune recovery. These data reinforce that early identification and treatment are warranted to improve clinical outcomes. 293 Inflammatory Biomarker Changes After Antiretroviral Treatment (ART) Initiation Konstantia Angelidou 1 ; PeterW. Hunt 2 ; AlanTenorio 3 ; Alan L. Landay 4 ; CaraWilson 5 ; Benigno Rodriguez 6 ; Steven G. Deeks 2 ; Ronald Bosch 1 ; Michael M. Lederman 7 1 Harvard Sch of PH, Boston, MA, USA; 2 Univ of California San Francisco, San Francisco, CA, USA; 3 GSK, Research Triangle Park, NC, USA; 4 Rush Univ, Chicago, IL, USA; 5 Univ of Colorado Hosp, Aurora, Aurora, CO, USA; 6 Case Western Reserve Univ Sch of Med, Cleveland, OH, USA; 7 Case Western Reserve Univ, Cleveland, OH, USA Background: Inflammatory cytokine levels pre- and one year post-ART were associated with incident non-AIDS events after one year in a nested case-control study of ACTG A5001. We examine changes in biomarkers after ART initiation. Methods: Stored plasma from pre-ART (Y0), year 1 (Y1) and at the visit preceding an event was tested for inflammatory biomarkers (IL-6, sTNFR-I, sTNFR-II, sCD14, D-dimer) in 142 cases (non-accidental non–AIDS death, MI, stroke, non–AIDS malignancy, serious bacterial infection) and 302 matched controls. Unadjusted and partial Spearman correlations evaluated among controls the associations between levels and changes of biomarkers with pre-ART factors: HIV-1 RNA (VL), CD4, CD4:CD8 ratio, CD8, age, waist-hip ratio (WHR). Associations of biomarker changes with non-AIDS events were evaluated by conditional logistic regression. Results: Median pre-ART age was 44 years; 85%were male; median Y0 CD4 215 cells/mm 3 and VL 64,371 copies/mL. Among controls: Higher biomarker levels at Y0 and Y1 (except for Y1 D-dimer) correlated with higher Y0 VL (p<0.05) and lower Y0 CD4 (p<0.05). All biomarkers declined from Y0 to Y1 (p<0.0001). Declines between Y0 and Y1 were greater for high Y0 VL (p<0.002) (Table), low Y0 CD4 (p<0.001) [even after Y0 VL adjustment] and low Y0 CD4:CD8 (p<0.001) [even after Y0 VL adjustment]. Older participants had greater declines for sTNFR-II, sCD14 and D-dimer from Y0 to Y1 (p<0.04). Those with higher WHR had greater declines in sCD14 and D-dimer from Y0 to Y1 (p<0.01). Though higher Y1 levels for all biomarkers were significantly associated with incident non-AIDS events (cases vs controls), greater declines in biomarkers at Y1 showed no significant associations. Cases, however, had significantly greater increases in all biomarkers from Y1 to the visit preceding the event (p<0.02). Effect of Acute HIV Infection on CD4/CD8 Normalization After ART Initiation Thibaut Davy ; Sonia Napravnik; Anna Cope; JoAnn D. Kuruc; Cynthia Gay; Joseph J. Eron Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Poster Abstracts

112

CROI 2016