CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

Background: Abacavir (ABC) use has been associated with increased risk of myocardial infarction (MI), with altered endothelial and platelet function as proposed underlying mechanisms. We hypothesized that a switch from ABC to tenofovir alafenamide (TAF) would result in decreased platelet reactivity. Methods: In a platelet function substudy of a randomized double-blind trial of virally suppressed, HIV1-positive individuals on ABC/lamivudine (3TC), randomized to switch to TAF/emtricitabine (FTC) or remain on ABC/3TC while continuing their 3rd agent, we measured platelet aggregation (PAg) at baseline (BL), week (W) 4, and 12 in response to increasing concentrations of five agonists: collagen (Col), thrombin receptor-activating peptide (TRAP), adenosine diphosphate (ADP), epinephrine (Epi) and arachidonic acid (AA). We compared population-derived agonist concentrations inducing 50% platelet aggregation (EC 50 ) between-groups at BL, W4 and 12 by four parameter logistic regression. We measured platelet surface expression of the GPVI receptor, CD42b and P-selectin (P-sel) by flow cytometry and compared between-group differences at BL and W12 pre- and post-stimulation with collagen-related peptide (CRP) by Wilcoxon rank sum test. Results: The 61 participants (29 in TAF/FTC and 32 in ABC/3TC group) were well matched at BL. Although baseline PAg in response to Col, TRAP and ADP was similar between groups, W4 PAg with Col, TRAP and ADP was significantly lower in the TAF/FTC arm (reflected by greater EC 50 ) compared to the ABC/3TC arm (Table). Reduced PAg in response to Col persisted through W12, while differences in PAg with TRAP and ADP were no longer significant at W12. PAg with Epi and AA did not differ between groups at any time point. Expression of the collagen receptor GPVI, which mediates endothelial-platelet interactions, was higher at W12 in the TAF/FTC group (P=0.031) while W12 GP42b and P-sel were similar between groups (P=0.10, P=0.8). There were no between-group differences in GPVI shedding or induction of P-sel with CRP activation (all P>0.1). Conclusion: Within a randomized trial, switching from ABC/3TC to TAF/FTC was associated with significantly lower platelet reactivity to TRAP and ADP at W4 and Col through W12. Together with higher surface GPVI expression, these observations suggest improvements in measures of platelet function involving endothelial-platelet pathways with a switch from ABC/3TC and point to a potential underlying mechanism for increased risk of MI with ABC.

79 IMPACT OF LDMTX ON IMMUNE ACTIVATION AND ENDOTHELIAL FUNCTION IN TREATED HIV Priscilla Hsue 1 , Heather Ribaudo 2 , Steven G. Deeks 1 , Michael M. Lederman 3 , Carl Fichtenbaum 4 , Annie F. Luetkemeyer 1 , Eric Daar 5 , Benigno Rodriguez 3 , Babafemi Taiwo 6 , David Haas 7 , Victoria Johnson 8 , James H. Stein 9 , Judith S. Currier 5 1 University of California San Francisco, San Francisco, CA, USA, 2 Harvard University, Cambridge, MA, USA, 3 Case Western Reserve University, Cleveland, OH, USA, 4 University of Cincinnati, Cincinnati, OH, USA, 5 University of California Los Angeles, Los Angeles, CA, USA, 6 Northwestern University, Chicago, IL, USA, 7 Vanderbilt University, Nashville, TN, USA, 8 University of Alabama at Birmingham, Birmingham, AL, USA, 9 University of Wisconsin, Madison, WI, USA Background: Chronic inflammation in treated HIV infection predicts mortality and non-AIDS morbidities including cardiovascular disease (CVD). Low dose methotrexate (LDMTX) is an anti-inflammatory drug that is associated with reduced risk of CVD in the RA population. We evaluated the safety and potential efficacy of LDMTX in treated HIV. Methods: This was a randomized placebo-controlled study in ART-treated HIV-infected individuals ≥40 years of age with or at increased risk for CVD and with CD4+ T-cells >400 cells/mm 3 . Participants received weekly LDMTX or placebo (+ folic acid) for 24 weeks and were followed for an additional 12 weeks. HIV disease indices, safety events, and endothelial function (ultrasound brachial artery flow-mediated dilation [FMD]) were assessed. The primary endpoints of this study were: 1) safety; 2) endothelial function, and 3) markers of inflammation/ immune activation. A5314 was powered to demonstrate no more than a 15% point higher rate of safety events with LDMTX and to detect a 1.5% difference in 24-week FMD change between groups. Results: The 176 participants had a median (Q1, Q3) age of 54 (49, 59) years, 90%were male, and median entry CD4+ T cells of 726 (552, 940) cells/mm 3 . Median change in CD4+ T-cells after 24 weeks was -58 (-163, 47) vs. 2 (-101, 97) cells/mm 3 in the LDMTX vs. placebo group (p=0.003) with partial rebound (p=0.09) by 36 weeks. Median change in CD8+ T-cells after 24 weeks was -103 (-228, 0) vs. -2 (-142, 84) cells/mm 3 in the LDMTX vs. placebo group (p=0.001). Safety event rates were 12.8% (11 events) with LDMTX vs. 5.6% (5 events) with placebo (Δ=7.2%, upper 1-sided 90% CI=13.4%). FMD did not improve with LDMTX (Δ=0.09% [95% CI -0.67%, 0.85%]); hsCRP, IP-10, IL-6, sCD14, sCD163, D-Dimer, Fibrinogen, and sVCAM also did not change with LDMTX. Across all study weeks, there were LDMTX-related decreases in the frequency of activated and proliferating CD8+ T cells (p<0.019). Conclusion: In older HIV-infected adults with CVD or at risk for CVD, we observed high rates of adverse events in both arms. These rates were higher with LDMTX but within the non-inferiority bound. LDMTX had no effect on endothelial function or soluble inflammatory markers. LDMTX-mediated declines in CD8+ T cell numbers, activation and proliferation suggest that the immunomodulatory effects of this drug are mediated through T cells and their activation state. Future studies to evaluate the impact of LDMTX on persistent T cell dysfunction are ongoing. 80 PLATELET FUNCTION UPON SWITCHING TO TAF VS CONTINUING ABC: A RANDOMIZED SUBSTUDY Patrick W. Mallon 1 , Alan Winston 2 , Frank Post 3 , Dermot Kenny 4 , Colm Bergin 5 , Robert T. Maughan 1 , Elena Alvarez-Barco 1 , Willard Tinago 1 , Eimear Dunne 4 , Mingjin Yan 6 , Moupali Das 6 , Martin Rhee 6 1 University College Dublin, Dublin, Ireland, 2 Imperial College London, London, UK, 3 King’s College Hospital NHS Foundation Trust, London, UK, 4 Royal College of Surgeons in Ireland, Dublin, Ireland, 5 St. James’s Hospital, Dublin, Ireland, 6 Gilead Sciences, Inc, Foster City, CA, USA

Oral Abstracts

81LB A TREATMENT AS PREVENTION TRIAL TO ELIMINATE HCV IN HIV+ MSM: THE SWISS HCVREE TRIAL Dominique L. Braun 1 , Benjamin H. Hampel 1 , Huyen Nguyen 1 , Markus Flepp 2 , Marcel Stoeckle 3 , Charles Béguelin 4 , Patrick Schmid 5 , Julie Delaloye 6 , Mathieu Rougemont 7 , Enos Bernasconi 8 , Dunja Nicca 3 , Roger Kouyos 1 , Jürg Böni 1 , Huldrych F. Günthard 1 , Jan S. Fehr 1 1 University of Zurich, Zurich, Switzerland, 2 Centre for Infectious Diseases, Zurich, Switzerland, 3 University of Basel, Basel, Switzerland, 4 University of Bern, Bern, Switzerland, 5 St. Gallen Cantonal Hospital, St Gallen, Switzerland, 6 Lausanne University Hospital, Lausanne, Switzerland, 7 University Hospitals of Geneva, Geneva, Switzerland, 8 Ospedale Regionale di Lugano, Lugano, Switzerland Background: Incidence of sexually transmitted hepatitis C virus (HCV) infections among HIV+men who have sex with men (MSM) is rising worldwide. The Swiss HCVree Trial (ClinicalTrials.gov NCT02785666) aimed to test the feasibility of a HCV elimination approach among HIV+MSM participating in the Swiss HIV Cohort Study (SHCS).

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CROI 2018