CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

1 Bellvitge University Hospital, Barcelona, Spain, 2 Hospital Clinic of Barcelona, Barcelona, Spain, 3 University of Gothenburg, Gothenburg, Sweden, 4 Innsbruck Medical University, Innsbrusk, Austria, 5 Bellvitge Biomedical Research Institute, Barcelona, Spain, 6 Medical University of Innsbruck, Innsbruck, Austria Background: A major concern of dual therapy is the potential lower efficacy in viral reservoirs, especially in the central nervous system (CNS). The aim of this study was to evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) in asymptomatic stable patients switching antiretroviral therapy within a clinical trial. Methods: Prospective, single arm study. HIV+ virologically suppressed patients on triple therapy were randomly selected to switch to Lamivudine 300 mg + Dolutegravir 50 mg once daily within the DOLAM Study (EUDRA CT 2015- 000274-35). A small group consented to participate in the Neuro-Substudy. All pts were on stable triple therapy and had no history of virological failure to regimens containing 3TC/FTC or INSTI as per inclusion/exclusion criteria. CSF and blood samples were taken at baseline and week 48. Plasma and CSF HIV-1 RNA were assessed by real-time PCR. CSF neurofilament light chain (NFL) as well as inflammatory markers (sTREM2, Neopterine, MCP-1, IL-6) were measured in CSF by sandwich ELISA method. Results: 15 pts had baseline and week 48 plasma and CSF samples. 12 (80%) pts were male. Median (IQR) age was 46 (14) years, baseline and nadir CD4 count 746 (356) and 302 (165) cells/μl respectively. Most patients switched from a NNRTI based regimen (60%) followed by INSTI (26.7%). All subjects maintained plasma viral suppression at baseline, week12, 24, 36 and 48. HIV RNA in CSF was undetectable at baseline and week 48 in all participants (LOD 40 copies/ml). NFL median change from baseline to week 48 was not statistically significant [Median (Min-Max) NFL at baseline: 499 ng/L(268-734); Median (Min-Max) NFL at W48: 457(226-886); p:0.3]. No significant changes were observed in the rest of inflammatory markers in CSF. Conclusion: Treatment simplification from triple therapy to Dolutegravir+Lamivudine resulted in no changes in viral suppression in plasma and CSF. No evidence of neuronal damage or changes in inflammatory markers were found in CSF after 48 weeks of dual therapy. These data suggest that dual therapy with Dolutegravir+Lamivudine maintains viral control within the CNS reservoir, but larger studies are needed. 436 BILIRUBIN AS A SURROGATE MARKER OF DOLUTEGRAVIR-ASSOCIATED CNS ADVERSE EVENTS Elena Alvarez-Barco 1 , Fergal Moran 1 , Ciara Levey 2 , Willard Tinago 1 , Patrick W. Mallon 1 1 University College Dublin, Dublin, Ireland, 2 Mater Misericordiae University Hospital, Dublin, Ireland Background: In Phase 3 trials, dolutegravir (DTG) was well tolerated, with only 2% prevalence of adverse events (AE) leading to discontinuation. However, in post-marketing data, use of DTG has been associated with central nervous system (CNS) events. Higher DTG plasma levels have previously been associated with CNS AE. Given that both DTG and bilirubin (BIL) are metabolised by the UGT1A1 enzyme, we aimed to assess if BIL levels, as a surrogate marker for DTG and UGT1A1 activity, could predict CNS effects with DTG. Methods: Analysis of subjects treated with DTG within the UCD ID Cohort, a prospective cohort study, with BIL levels recorded pre and at weeks 4, 12, 48 and 96 after DTG initiation. Reported CNS AE were obtained at same time points. Subjects were divided into those who did or did not reported CNS AE (CNS group vs no-CNS groups). Between group differences in BIL levels were assessed using Mann-Whitney tests and linear mixed effects model as appropriate. Contribution of BIL levels to development of CNS AE was assessed using logistic regression models. Results: 372 subjects were included in the study, mean age (SD) 44.6 (9.3) years, 59%males, 61% Caucasian, 28% acquired HIV via intravenous drug use, median CD4-T cell count 515.5 (IQR 321, 720) cells/mm 3 , 66% HIV RNA<40c/ mL, 14% co-infected with HCV and 3% co-infected with HBV. A total of 102 (33%) subjects reported AE, of which 94%were CNS AE, with insomnia (40%), depression (15%) and headache (15%) most commonly reported. Median (IQR) time to develop CNS AE was 17 (5, 51) weeks. Although no between-group differences were observed in changes of BIL levels overtime (p=0.79), BIL levels at the time of reporting CNS AE were significantly higher in the CNS group compared to the same time point from non-CNS subjects matched by age and gender (mean (SD) 12.3 (8.9) vs 9.4 (5.9) µmol/L, p=0.02). In analysis adjusted

434 ROLE FOR PLATELET ACTIVATION AND ENDOTHELIAL ASSOCIATION IN HIV ENTRY INTO THE BRAIN Claire E. Lyons 1 , Hannah Schneider 1 , Elizabeth L. Engle 1 , Kevin M. Najarro 1 , Suzanne E. Queen 1 , Craig N. Morrell 2 , Joseph Mankowski 1 , Kelly A. Metcalf Pate 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 University of Rochester, Rochester, NY, USA Background: The brain is an important sanctuary site and barrier to cure in HIV. Platelet decline is associated with perivascular cuffs of infected cells in the brain in HIV infected humans and SIV infected macaques, but is considered subclinical and often untreated. Platelet activation and interactions with vascular endothelium can contribute to platelet decline, and impact the permeability of the blood brain barrier in the context of other diseases. We sought to determine if platelet-endothelial associations (PEAs) contribute to platelet decline and are associated with the presence of infiltrates of infected cells in the brain in the SIV-infected pigtailed macaque model of HIV infection, to confirm that PEAs exist in people living with HIV (PLWH), and to define how these interactions affect the blood brain barrier. Methods: The effect of platelets on microvascular endothelial integrity in the brain was determined using a transwell cell culture assay system. PEAs and perivascular macrophages in the brain were identified using immunohistochemistry on tissue from SIV-infected pigtailed macaques and uninfected controls and from PLWH, and associations between PEAs and macrophage subsets determined using unbiased stereology. Platelet activation was monitored throughout infection using flow cytometry of platelet p-selectin on peripheral blood. Results: Permeability of brain microvascular endothelium (BMEC) decreased two-fold following incubation with platelets from SIV-infected macaques compared with uninfected macaques (P=0.01), and that effect was abrogated by preventing contact between the platelets and BMECs. PEAs were observed in the brains of PLWH and in SIV-infected macaques. PEAs were more common in SIV-infected than control macaques during acute (RR = 4.0, P = 0.03) and asymptomatic (RR = 3.6, P = 0.04) infection, and were more likely to be associated with blood vessels surrounded by SIV-infected non-resident macrophages (RR = 1.5, P = 0.007). Macaques that did not develop perivascular infiltrates of cells in their brains during terminal infection demonstrated higher platelet activation during acute (P = 0.04) and asymptomatic (P < 0.0001) infection compared to those that developed infiltrates. Conclusion: Platelet activation and PEA formation may represent a protective mechanism against entry of SIV-infected cells into the brain. Platelet decline in HIV infection may have clinical impacts and contribute to the development of latent viral reservoirs. 435 HIV SUPPRESSION AND CHANGES IN CSF MARKERS IN PATIENTS RANDOMLY SWITCHED TO DTG + 3TC Juan M. Tiraboschi 1 , Jhon Rojas 2 , Henrik Zetterberg 3 , Jordi Niubo 1 , Johanna Gostner 4 , Antonio Navarro-Alcaraz 5 , Camila Piatti 5 , Dietmar Fuchs 6 , Magnus Gisslén 3 , Esteban Martinez 2 , Daniel Podzamczer 1

Poster Abstracts

CROI 2020 152