CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

were not present in this broader cohort of HIV infected individuals. Earlier intervention or longer duration of RFX therapy may be necessary to affect IA. 314 EFFECT OF SWITCHING TO RALTEGRAVIR AND/OR ADDING LOSARTAN ON HIV IMMUNE ACTIVATION Berta Torres 1 , Alberto C. Guardo 2 , Amanda Fabra 2 , Lorna Leal 1 , Cristina Rovira 2 , Carmen Hurtado 2 , Manel E. Bargalló 2 , Constanza Lucero 1 , Irene Fernandez 1 , Flor Etcheverry 1 , Jose M. Gatell 1 , Montserrat Plana 2 , Felipe Garcia 1 1 Hospital Clinic of Barcelona, Barcelona, Spain, 2 IDIBAPS, Barcelona, Spain Background: Inflammation and immune activation markers associated with end-organ diseases like atherosclerosis are higher in treatment-suppressed HIV patients than in non-HIV population. No therapies have been developed to effectively target these mediators. A decrease of immune activation markers after raltegravir intensification and anti-inflammatory properties of the angiotensin receptor antagonist losartan have been reported. The objective of this clinical trial was to investigate the effect of switching to raltegravir and/or adding losartan on the inflammatory/immune-activation mediators in treated HIV patients Methods: 48 chronic HIV patients successfully treated with 2 NRTI and 1 NNRTI or PI during at least 48w were randomized to: continue the same ART (n=12), switch NNRTI/PI to raltegravir (n=12), add losartan (n=12) or switch NNRTI/PI to raltegravir and add losartan (n=12) for 48w. Markers of T CD4 and CD8 lymphocytes activation (HLADR+38+) and senescence (CD28-CD57+), monocyte activation (CD14+, CD16+) and inflammation (hsCRP, TNF-alpha, D-dimer and IL-6) were determined at baseline and at w48 and compared between groups. Results: Median age was 41 years. The median (IQR) time since diagnosis was 8 (5-11) years and patients were on successful ART for a median (IQR) 5 (3-10) years. Median (IQR) nadir, baseline CD4 count and CD4/CD8 ratio was 307 (221-390), 723 (571-927) c/mm 3 and 0,93 (0,6-1,2), respectively. Patients who switched to raltegravir showed a higher decrease in all activated [CD4+38+HLADR+ -1,3 vs -0,6 (p=0.033); CD8+38+HLADR+ -1.6 vs 1.3 (p=0.02)] and senescent [CD4+28-57+ -0.3 vs 0.26 (p=0.04); CD8+28-57+ -6.1 vs 3.8 (p=0.002)] T lymphocyte populations than those who did not change ART. CD4/CD8 ratio increased a median of 0.35 in patients in the raltegravir group vs 0.03 in patients not taking raltegravir (p=0.002). No changes were observed in patients allocated to losartan. Differences between groups in monocyte subpopulations or inflammation markers were not observed. Conclusion: Switching a NNRT/PI containing regimen to raltegravir significantly improved immune system as measured by a decrease in activated and senescent T lymphocyte subpopulations and an increase in CD4/ CD8 ratio in successfully treated HIV patients. Conversely, adding losartan did not have any impact on inflammation or T cell/monocyte activation or senescence. 315 TLR9 AGONIST ENHANCES B CELL DIFFERENTIATION AND ANTIBODY PRODUCTION IN HIV+ ADULTS Mariane H. Schleimann 1 , Line K. Vibholm 1 , Maria-Louise R. Kobberø 1 , Manuel Schmidt 2 , Burghardt Wittig 3 , Tine Damsgaard 1 , Peter Ahlburg 1 , Michel Hellfritzsch 1 , Rikke Olesen 1 , Lars Østergaard 1 , Paul W. Denton 1 , Martin Tolstrup 1 , Ole S. Søgaard 1 1 Aarhus University Hospital, Aarhus, Denmark, 2 Mologen AG, Berlin, Germany, 3 Freie Universität Berlin, Berlin, Germany Background: HIV-infected individuals greatly suffer from B cell dysfunction, partly due to increased fibrosis and destruction of lymph node architecture. As we test curative strategies for HIV it is apparent that an improvement of the immune system is a necessity. To boost immunity, we treated HIV+ individuals with the TLR9 agonist lefitolimod (MGN1703). Here we report the effects on B cell differentiation as well as total plasma IgG levels as it has been shown that TLR9 agonists stimulation of B cells lead to enhanced humoral immunity. Methods: We performed a single-arm phase 1b/2a clinical trial, where 13 HIV+ adults on ART received lefitolimod (60 mg s.c.) twice weekly for 24 weeks (NCT02443935). We analyzed B cell differentiation status on freshly isolated PBMCs (baseline, on weeks (wk)12 and 24) and on freshly isolated mononuclear cells from lymph nodes (baseline, wk24) via flow cytometry. We also analyzed total plasma IgG and IgG subtypes using a standard clinical assay. On-drug time- points were compared to baseline using Wilcoxon signed-rank test. Results: B cell differentiation and maturation can be identified through multiple phenotypic stages. We examined key B cell subsets and found a

313 RIFAXIMIN USE DOES NOT ALTER SCD14 LEVELS IN HIV-INFECTED PERSONS ON SUPPRESSIVE ART

Poster Abstracts

Anuradha Ganesan 1 , Deborah McMahon 2 , Netanya S. Utay 3 , Jennifer Bell 4 , Heather Burris 1 , Timothy Whitman 5 , Jing Qin 6 , Jeffrey Laczek 5 , Patrick Young 5 , Brian K. Agan 1 , Sheila Kumar 7 , Dean Follmann 6 , Stephen Wank 7 , Frank Maldarelli 8 1 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 2 University of Pittsburgh, Pittsburgh, PA, USA, 3 University of Texas at Houston, Houston, TX, USA, 4 Leidos Biomedical Research, Inc, Frederick, MD, USA, 5 Walter Reed National Military Medical Center, Bethesda, MD, USA, 6 NIAID, Bethesda, MD, USA, 7 NIH, Bethesda, MD, USA, 8 NCI, Rockville, MD, USA Background: Immune activation (IA) plays a central role in the pathogenesis of HIV infection. A potential driver of IA is the translocation of gut microbial products. Elevated levels of soluble CD14 (sCD14) are associated with all- cause mortality in HIV-infected persons. One source of elevated sCD14 is lipopolysaccharide (LPS) exposure from gut bacteria. Rifaximin (RFX) is an oral, non-absorbable systemic antibiotic that reduces serum LPS levels. Previously, RFX had a modest effect on cellular IA markers in HIV infected immune non- responders (Tenorio, 2015). We sought to study the effects of RFX on sCD14 levels in chronically suppressed HIV-infected persons. Methods: In this double blind, multicenter, randomized crossover clinical trial HIV infected persons on suppressive ART (< 50 cps/mL, ≥3 years), were randomized to receive either RFX 550 mg or placebo twice daily for 28 days. After a 4-6 week wash-out participants switched treatment arms completing an additional 28 days of study treatment. The study had 95% power to detect a 0.20 pg/mL difference in sCD14 levels. CD38 and HLA-DR expression on CD4+ and CD8+ T cells was used to measure IA. To assess treatment effects, we calculated the difference in changes, for all parameters, for the participants. We tested the hypothesis that the median differences of these changes were zero using a paired Wilcoxon test. Results: Of 42 randomized participants, 37 had evaluable results (median age 47y, 92%male, 32% African-American, median baseline CD4 count 646 cells/ uL; 2 participants were non-responders). The median baseline sCD14 level was 1.45 mcg/ml (range 0.86-3.0). The median change in plasma sCD14 levels during the RFX and placebo phases of the study were 0.07 (IQR -0.10, 0.22) mcg/ mL and 0.00 (-0.19, 0.15) mcg/mL respectively, with no significant change in plasma sCD14 levels (p=0.51). We found no change in the frequency of CD4+ or CD8+ cells expressing HLA-DR, CD38, or both with the use of RFX. An additional statistical test to assess drug carryover revealed no differential effect by period, (p=0.661). Conclusion: Short term RFX in HIV infected persons taking ART with a median CD4 count >500 cells/uL did not reduce sCD14 levels or result in changes in cellular IA; reductions in IA noted previously in immune non-responders

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