CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Palomino 2 , Carlos Nicolau 1 , Jose M. Gatell 3 , Felipe Garcia 1 , Montserrat Plana 2 , for the DCV-3/RISVAC04 Study Group 1 Hospital Clinic of Barcelona, Barcelona, Spain, 2 IDIBAPS, Barcelona, Spain, 3 ViiV Healthcare, Madrid, Spain Background: A double-blind placebo-controlled randomized therapeutic vaccine trial with myeloid derived-dendritic cells (MD-DC) loaded with heat- inactivated autologous HIV-1 (HIAH) plus pegylated Interferon-alpha (pIFN) in HIV-1 chronic infected patients on antiretroviral treatment (ART) to achieve functional cure was performed. Methods: 36 patients on successful ART with CD4+≥450 cells/mm 3 were randomized 1:1:1:1 and 29 received at w0, 2 and 4 an ultrasound-guided inguinal intranodal dose of: 1) vaccine (V) 107 MD-DC pulsed with 1010 HIAH (n=8); 2) V plus 3 doses of pIFN (VpIFN) at w4, 5 and 6 (n=6); 3) placebo (P) (n=7); and 4) P plus 3 doses of pIFN (PpIFN) at w4, 5 and 6 (n=8). ART was interrupted (ATI) at week 4. The primary end-points were safety and proportion of patients with undetectable VL 12w after ATI (w16). Secondary end-points were DVL set-point (set-point ATI-preART), and DHIV-1 specific T cell responses (IFN- ƴ Elispot) (w16-w0). Results: All participants were male. The procedure was safe and well tolerated. All patients had detectable VL at w16. DVL set-point [log 10 mean (SE) copies/ ml) was: 1) V 0,20 (0,21) 2) VpIFN -0.44 (0,38) 3) P -0,19 (0,23) 4) PpIFN -0,17 (0,20) (p=0.37). A decrease >1log 10 in VL set-point was seen in 0, 3, 1 and 0 patients in V, VpIFN, P and PpIFN, respectively (p=0.05 and p= 0.06 for the differences between VpIFN vs V, and VpIFN vs PpIFN, respectively). At baseline, HIV-1 specific T-cell responses were lower in vaccines vs placebo groups [mean (SE) 900 (200) vs 2259 (535) SFC/10 6 PBMC, p=0.028). No significant differences in DHIV-1 specific T-cell responses were observed between vaccine and placebo groups (p=0.09). No effect on T cell responses was observed with pIFN administration. A trend to significative negative correlation between DVL and DHIV-specific T-cell responses (w16-w0) was observed in vaccine and not in placebo groups (r=-0.56, p=0.09; r-028, p= 0.43; vaccine and placebo groups, respectively). Conclusion: The combination of a MD-DC therapeutic vaccine and pegIFNα was safe. A very modest decrease in VL was observed in vaccine recipients and was correlated with an increase of HIV-1 specific T-cell responses. Clinical trial.gov EudraCT 2015-001795-22 Lorena Vigón 1 , Sara Rodríguez-Mora 1 , Elena Mateos 1 , Valentín García 2 , Juan Ambrosioni 3 , Virginia Sandonís 4 , Guiomar Bautista 5 , Pilar Pérez-Romero 1 , José Alcamí Pertejo 1 , Juan Luis Steegmann 6 , Jose M. Miro 3 , Vicente Planelles 7 , María Rosa López-Huertas 1 , Mayte Coiras 1 1 Institute of Health Carlos III, Madrid, Spain, 2 Hospital Ramón y Cajal, Madrid, Spain, 3 IDIBAPS, Barcelona, Spain, 4 Hospital Universitario 12 de Octubre, Madrid, Spain, 5 Hospital Puerta de Hierro, Madrid, Spain, 6 Hospital Universitario de La Princesa, Madrid, Spain, 7 University of Utah, Salt Lake City, UT, USA Background: Tyrosine kinase inhibitors (TKIs) are used in clinic to treat chronic myeloid leukemia (CML). TKIs should be taken for life but some patients stop treatment due to antileukemic deep molecular response (DMR). Some TKIs may also induce a potent immune response against CMV and our group described an inhibition of HIV infection in vitro and in vivo. Many mechanisms define TKIs activity against HIV: 1) cytostatic effect and inhibition of cytokine-dependent proliferation, possibly affecting reservoir establishment and replenishment 2) maintenance of SAMHD1antiviral activity 3) sustained cytotoxic activity to control the growth of cancerous cells even after withdrawal. Objectives: 1) to analyze cytotoxic effect in CML patient cell populations during TKI treatment and after withdrawal; 2) to determine the susceptibility to HIV infection of CD4 T cells from CML patients off TKI treatment. Methods: PBMCs from CML patients on TKI treatment for avg. 3.8±0.5y (dasatinib n=20; imatinib n=11; nilotinib n=9; bosutinib n=5; ponatinib n=1), CML patients off TKI treatment for avg. 2.3±0.3y due to DMR (last TKI: dasatinib=4; imatinib=7; nilotinib=6) and healthy donors (n=30) were analyzed by flow cytometry. IFNg synthesis was analyzed by flow cytometry and proviral integration by Alu-qPCR. Results: 1) Active NK cells CD56+CD16+CD107a+ were increased >6-fold in patients on treatment with all TKIs except imatinib, compared to control. This population remained >5-fold enhanced after withdrawal. 2) CD8±TCRgd+ lymphocytes were increased >2-fold in patients on treatment and remained

>3-fold greater in patients off treatment. 3) Synthesis of IFNg in response to in vitro CMV pp65 peptide was increased >2-fold in CD8+CD69+ T cells from patients off treatment. However, no CD8 reactivation was detected in patients on treatment probably due to the potent cytostatic effect of TKIs. 4) In vitro treatment with TKI dasatinib and IL-15 increased >2.5-fold the IFNg secretion from NK cells. 5) PBMCs from patients off treatment showed <12-fold proviral integration after in vitro infection Conclusion: TKIs induce mechanisms with antiviral activity that may be used against HIV infection. Populations of active NK cells and IFNg-secreting CD8 cells may persist in CML patients even after treatment withdrawal, as well as CD4 cells resistant to HIV infection. These results suggest a possible transient use of TKIs in HIV-infected patients to establish a persistent antiviral activity 284 RATIONAL DONOR FECAL MICROBIOTA TRANSPLANTATION IN HIV (REFRESH STUDY) Sergio Serrano-Villar 1 , Alba Talavera 2 , Nadia Madrid-Elena 2 , José A. Pérez- Molina 1 , María José Gosalbes 3 , Shrish Budree 4 , Alejandro Vallejo 2 , Ryan J. Elliott 4 , Fernando Dronda 1 , Carolina Gutiérrez 2 , María J. Vivancos-Gallego 1 , Javier Martínez-Sanz 1 , Sabina Herrera 1 , Raquel Ron 1 , Santiago Moreno 1 1 Hospital Ramón y Cajal, Madrid, Spain, 2 Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain, 3 FISABIO, Valencia, Spain, 4 OpenBiome, Cambridge, MA, USA Background: It is unknown whether oral fecal microbiota transplants (FMT) can affect the gut microbiota and systemic immunity of HIV-infected individuals. Methods: Thirty ART-treated HIV-infected subjects with a CD4/CD8 ratio <1 were allocated to receive either weekly oral fecal microbiota capsules or placebo for 8 weeks (10 capsules at week 0; 5 capsules/week fromweeks 1-7). Three stool donors were selected from a universal donor stool bank based on bacterial abundance of Fecalibacterium and Bacteroides (high) and Prevotella (low) and high fecal butyrate concentrations. We assessed 48-week safety and efficacy, including changes in CD4/CD8 T cells, microbiota engraftment using Illumina 16S rDNA sequencing, T cell activation/senescence, inflammation (sCD14, sCD163, sTNFr-2), bacterial translocation (LTA, LBP) and intestinal damage (FABP2) markers. Results: Twenty-nine participants, with a mean CD4 count of 641±286 cells/ μL completed the 48-week follow-up. FMT was well tolerated, with no grade 3-4 related adverse events. No significant changes were observed in CD4/CD8 T-cells, in T-cell activation/senescence or levels of the inflammation/bacterial translocation markers. Significant between-group differences were observed in FABP2, with higher fold change decrease at week 4 in the FMT arm (0.52 vs. 0.95, p=0.045). Alfa diversity significantly and incrementally increased until week 6 in the FMT arm (FMT vs. placebo arm, p=0.013) and returned to baseline levels at week 48. Unifrac distance trajectories indicated mild engraftment of donor’s microbiota that persisted until week 36 and greater engraftment among the 4 subjects who had received antibiotics in the 12-week period before FMT. LEfSe analyses showed an incremental engraftment of different taxa in the active arm, being Lachnospiraceae family and Faecalibaculum, Faecalicoccus, Fusicatenibacter, Anaerostipes and Ruminococcus genus the taxa more robustly engrafted across time-points. Conclusion: Repeated oral capsular FMT was safe in HIV-infected subjects on ART and introduced incremental compositional changes in the microbiota. While it is unclear whether this strategy will help to attenuate systemic inflammation, our results indicate that manipulation of the gut microbiota using a non-invasive and safe strategy of FMT delivery is feasible.

Poster Abstracts

283 PERSISTENT ANTIVIRAL EFFECT INDUCED BY TYROSINE KINASE INHIBITORS

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CROI 2020