CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

37LB SAFETY, TOLERABILITY AND IMMUNOLOGIC ACTIVITY OF RUXOLITINIB ADDED TO SUPPRESSIVE ART Vincent C. Marconi 1 , Carlee Moser 2 , Christina Gavegnano 1 , Athe Tsibris 3 , Amy Kantor 2 , Edgar T. Overton 4 , Charles W. Flexner 5 , Peter W. Hunt 6 , Rafick-Pierre Sekaly 7 , Carlos del Rio 1 , Michael M. Lederman 7 , Randall Tressler 8 , Steven G. Deeks 6 , Jeffrey J. Lennox 1 , Raymond F. Schinazi 1 1 Emory University, Atlanta, GA, USA, 2 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 3 Harvard Medical School, Boston, MA, USA, 4 University of Alabama at Birmingham, Birmingham, AL, USA, 5 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 6 University of California San Francisco, San Francisco, CA, USA, 7 Case Western Reserve University, Cleveland, OH, USA, 8 NIH, Bethesda, MD, USA Background: Chronic inflammation is associated with end-organ disease and mortality for people living with HIV (PLWH). Ruxolitinib (RUX) is a Janus kinase (Jak) 1/2 inhibitor that reduced biomarkers of systemic inflammation in HIV-uninfected individuals, and HIV reservoir and persistence markers ex vivo. The goal of this trial was to determine the safety and efficacy of RUX in treated HIV disease. Methods: ACTG 5336 was an open-label, multi-site, randomized controlled trial of RUX (10 mg BID) for 5 weeks plus continuing ART versus ART alone. Eligible participants were suppressed on ART for > 2 years, CD4+ T cells >350 cells/µL, and had no current diagnosis or history of significant medical comorbidities. Primary tolerability and safety outcomes were premature RUX discontinuation and occurrence of any pre-defined safety event. Mean changes in plasma levels of IL6 (primary efficacy outcome), sCD14, and circulating CD4 and CD8 counts were compared between arms with t-tests. Plasma HIV-1 RNA levels were measured by integrase single copy assay (iSCA) with a limit of detection of 0.4 cpm. GEE models for binary data compared changes between arms. Results: Sixty participants enrolled (80%men, median age 44 yrs and CD4 count 737 cells/ µL; n=40 RUX and n=20 ART alone). Primary safety events occurred in 2.5% in RUX arm and 0% in control arm (Fisher’s, p=0.67). Three participants prematurely discontinued RUX due to participant request, unrelated syncope, and a grade 3 increased AST. At week 4/5, there was a non-significant decrease in IL6 in the RUX arm compared to control arm (mean fold change (FC) 0.93 vs 1.10, p=0.18), but a significant decrease in sCD14 in the RUX vs control arm (mean FC 0.97 vs 1.10, p=0.03). Those on RUX had a similar likelihood of iSCA < 0.4 cpm compared to control (relative risk = 0.98, p=0.94). In the RUX arm, CD4 and CD8 cell counts increased significantly at week 2 (mean Δ 131 and 162 cells/µL) and compared to control arm (p=0.01); at week 5, CD8 counts returned to baseline while CD4 counts remained elevated in the RUX arm. Conclusion: In a highly selected cohort of HIV-positive adults on suppressive ART, RUX was safe and well tolerated but did not significantly reduce IL6 levels. On RUX treatment there was a modest decrease in sCD14 with an increase in circulating T cells through mechanisms undefined. This proof-of-concept trial provides a rationale for future studies of Jak inhibitors in PLWH who have residual inflammation or immune dysfunction despite long-term suppressive ART.

ug/L in the placebo arm and 41.0 (-94.1, 176.2) ug/L in the Visbiome ES arm, but these changes were not statistically different (p=0.60). Similarly, there were no significant differences in changes in D-dimer, KT ratio, CD4 cell counts, CD4/CD8 ratio between the arms. Conclusion: Visbiome ES was safe and well tolerated among this cohort. No significant effect of Visbiome ES on systemic inflammatory markers was identified. While high loss to follow up in the placebo arm limits the strength of our conclusions, these results do not support Visbiome ES as a viable strategy to reduce systemic inflammation in suppressed PWH with preserved CD4 counts. 36 FACTOR X INHIBITION REDUCES COAGULATION BUT NOT INFLAMMATION IN PERSONS WITH HIV Jason V. Baker 1 , Julian Wolfson 2 , Tess Peterson 2 , Kelly Garcia-Myers 1 , Jonathan Klaphake 1 , Micah Mooberry 3 , Matthew Gissel 4 , Kathleen Brummel-Ziedins 4 , Irini Sereti 5 , Nigel Key 3 , Russell Tracy 4 1 Hennepin Healthcare Research Institute, Minneapolis, Minnesota, 2 University of Minnesota, Minneapolis, MN, USA, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 University of Vermont, Colchester, VT, USA, 5 NIAID, Bethesda, MD, USA Background: Activation of coagulation among persons with HIV is associated with a broad spectrum of end-organ disease risk, but the underlying pathogenesis is not well characterized. We hypothesized that hypercoagulation contributes to disease, in part, via upregulation of inflammatory pathways, in addition to direct effects from thrombogenesis. Methods: Treatment effects of oral edoxaban (30mg), a direct factor Xa inhibitor, versus placebo were investigated in a randomized, double-blind, cross-over clinical trial, among participants with HIV receiving ART with plasma HIV RNA <200 copies/mL and D-dimer levels ≥100 ng/mL. Blood specimens were collected twice prior to receiving study drug and then monthly during each 4-month cross-over treatment period. Soluble biomarkers (Table) were measured using ELISA, electrochemiluminescence, and immunoturbidmetric methods. The treatment effect, defined as change on edoxaban versus change on placebo, was calculated with linear mixed models for biomarkers (ln- transformed) and clinical labs (untransformed). Results: Forty-four participants were randomized among 83 screened; 40 completed the first period and 37 completed the second period. Mean age was 49 years and CD4+ count was 739 cells/mm3; 91%were male, 70%white, 36% current smokers, 34%with prior AIDS, and 70% had an integrase inhibitor- based ART regimen. Table 1 reports the treatment effect of edoxaban versus placebo on soluble biomarkers. Edoxaban treatment demonstrated a consistent reduction in coagulation activity; relative changes were -42% for D-dimer, -26% for TAT, and 7% for INR. There was no evidence of a significant treatment effect on the inflammatory biomarkers evaluated. Adherence was quantified as percent of days adherent (among the 92% that returned study drug) and did not differ between edoxaban (94%) and placebo (97%) periods. More non- laceration bruising or bleeding events occurred during edoxaban (28 among 17 persons) than during placebo or no drug periods (15 among 13 persons). All non- laceration bleeding events were either grade 1 (93%) or grade 2 (7%), and the most common were bruising (28%), epistaxis (23%), and bleeding gums (30%). Conclusion: The oral direct factor Xa inhibitor edoxaban substantially reduced coagulation activity among persons with HIV receiving ART with viral suppression. In this study, no effect on soluble systemic inflammatory markers was observed and there was an increased risk for minor bruising and bleeding events.

Oral Abstracts

38LB WITHDRAWN / INTENTIONALLY UNASSIGNED 39LB RANDOMIZED TRIAL OF RALTEGRAVIR-ART VS EFAVIRENZ-ART WHEN INITIATED DURING PREGNANCY Mark Mirochnick 1 , David E. Shapiro 2 , Leavitt Morrison 2 , Lisa Frenkel 3 , Nahida Chakhtoura 4 , George K. Siberry 5 , Brookie Best 6 , Maria Leticia S. Cruz 7 , Blandina T.

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CROI 2019