CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

the CD8 subset (between-groups differences, P=ns.). T-cell activation significantly decreased in all compartments during the study, and no differences among groups were appreciated. However, in duodenum, the MVC+RAL group exhibited opposite effects to the EFV group on the naïve/memory CD8 T-cell ratio ( Figure 1B , P=0.014), %naïve (P=0.018) and activated naïve CD8 T-cells (P=0.001), which increased in the MVC+RAL group but decreased in the EFV group. Similarly, peripheral CCR5+ CD4 and CD8 T cells significantly recovered up to normal levels in the MVC+RAL arm, while decreased in the EFV arm (MVC+RAL vs. EFV, P=0.003 and P=0.002, respectively).

Conclusions: These data suggest that quadruple ART including RAL+MVC may more effectively reach duodenum and improve systemic markers of innate immune activation and gut barrier. These therapeutic strategies deserve further assessment in clinical trials. 548 Maraviroc-Dependent Pharmacologic Effects on Viral Decay and Immune Recovery in GALT Corbin Thompson 1 ;TaeWook Chun 2 ; Craig Sykes 1 ; Zhing-Min Ma 4 ; Christopher Miller 4 ; Surinder Mann 3 ; Richard Pollard 3 ; Angela Kashuba 1 ; David Asmuth 3 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, US; 2 Division of AIDS, NIAID, NIH, Bethesda, MD, US; 3 University of California Davis Medical Center, Davis, CA, US; 4 University of California Davis, Davis, CA, US Background: Immune recovery after antiretroviral (ARV) treatment is incomplete in many tissues such as gut-associated lymphoid tissue (GALT), which may allow for persistent HIV replication. Maraviroc (MVC) and raltegravir (RAL)-based regimens are associated with higher increases in peripheral CD4+ T cells and a more rapid decline in plasma viremia than other regimens, which make them favorable candidates to improve immune recovery and hasten viral decay in GALT. Here, we examine the effect of local ARV concentration on immune and viral dynamics in GALT, and determine whether MVC and/or RAL offer an improvement over NNRTI-based regimens. Methods: This was a prospective, randomized trial in 26 HIV positive, treatment naïve subjects receiving emtricitabine (FTC) plus tenofovir (TFV) in combination with an NNRTI (efavirenz n=6, nevirapine n=2), MVC (n=10), or MVC + RAL (n=8). Plasma and tissue (duodenum and colon) samples were collected at baseline and 9 months, and CD4+ T cells (flow cytometry), HIV RNA (rtPCR), and intracellular and extracellular drug concentrations (LC-MS/MS) were measured. Paired t-tests and ANOVA were used to assess within- and between-group comparisons, respectively. Associations between variables were made using linear regression. Data are reported as mean change +/- standard deviation; p<0.05 was considered significant. Results: At 9 months, all cohorts showed significant decreases (p<0.001) in HIV RNA in plasma (-3.69 ± 0.75 log copies/mL), duodenum (-1.48 ± 1.32) and colon (-3.25 ± 0.99), which were not significant between treatment arms (p>0.05). Treatment with MVC+RAL increased duodenal CD4+ T cells from baseline (+106.2 ± 79.1 cells/mm 3 , p=0.007). Mean FTC and TFV tissue exposure was 7.2 and 414.7% of plasma and not significant between groups. NNRTI, MVC, and RAL tissue exposure were 407.1, 79.6, and 6.8% of plasma, respectively. Duodenal concentrations of intracellular FTCtp were associated with greater recovery of CD4+ T cells (r=0.91, p<0.001) in the MVC cohort and a greater decrease in HIV RNA (r=0.72, p=0.04) in the MVC+RAL cohort. Conclusions: The restoration of GALT immune cells and reduction in HIV RNA agrees with plasma data, and did not differ between treatment groups. The beneficial effects of FTCtp in the duodenumwere observed only in the MVC cohorts, despite all treatment groups having similar concentrations. Taken together, these data suggest that MVC may be an Jori Symons 1 ;Ward de Spiegelaere 2 ; AnnemarieWensing 1 ; Julia Drylewicz 3 ; Ananja Middel 4 ; Andy I. Hoepelman 4 ; KikiTesselaar 3 ; LinosVandekerckhove 2 ; Steven F. van Lelyveld 4 ; Monique Nijhuis 1 1 University Medical Center Utrecht, Utrecht, Netherlands; 2 Ghent University, Ghent, Belgium; 3 University Medical Centre Utrecht, Utrecht, Netherlands; 4 University Medical Centre Utrecht, Utrecht, Netherlands Background: Recent data indicated that addition of maraviroc (MVC) to combination antiretroviral therapy (cART) increases immune activation. We investigated MVC induced cell activation and HIV production both in vivo during a MVC intensification trial and in vitro in donor peripheral blood mononuclear cells (PBMCs). Methods: Using ultra-sensitive droplet digital PCR detailed longitudinal virological and immunological analysis was performed in 15 immune non-responders participating in a 48-week, double-blind, placebo-controlled MVC intensification trial. We assessed changes in total HIV DNA, 2-LTR circles, HIV RNA expression and NF- κ B regulated gene expression (TNF-a, IFN-y, IL-10 and IL-6) per million PBMCs. Plasma levels of CCR5 ligands and immune activation markers (IL-2R, IP-10, sICAM and TWEAK) were analyzed by Luminex. Healthy donor PBMCs were infected with X4-tropic virus (HXB2) in absence or presence of increasing MVC levels and CA-p24 production was measured in culture supernatant. Results: Patient characteristics, immunological and virological baseline values did not differ between the MVC intensification and placebo group. During the first eight weeks of intensification, a significant difference in relative HIV RNA expression was detected (MVC increase 1.7 fold (n=10); placebo decrease 4.2 fold (n=5); p=0.03). After eight weeks we also measured a 2.3 fold increase in plasma CCR5 ligand MIP-1 β in the MVC group. During this period, a significant difference in NF-kB regulated gene expression was observed; expression increased in the MVC group and decreased in the placebo group (IFN-y p=0.02; IL-6 p=0.03). No differences in total cellular HIV DNA, 2-LTR circles and plasma activation markers were observed. In vitro assays demonstrated a significant dose-dependent increase in HIV production when MVC was added to PBMCs (2.2 fold). This significant increase in virus production was observed in all experiments (n=9) and at all dosages used (ranging from 1pM–1uM). important component of ARV regimens designed to improve virus decay and immune recovery in GALT. 549 Maraviroc Induces HIV Production in RCT and In Vitro, Potentially via the NFkB Pathway

Poster Abstracts

354

CROI 2015