CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

552

No Neurocognitive Benefit of Tesamorelin Immediate vs Delayed Treatment in Virally-Suppressed PWH Ronald J Ellis 1 , Florin Vaida 1 , Keren Hu 1 , Michael Dube 2 , Brook Henry 1 , Felicia C. Chow 3 , Lee Daniel 1 , Fred R. Sattler 4 1 University of California San Diego, La Jolla, CA, USA, 2 AIDS Healthcare Foundation, Los Angeles, CA, USA, 3 University of California San Francisco, San Francisco, CA, USA, 4 University of Southern California, Los Angeles, CA, USA Background: In people with HIV (PWH) who are virally suppressed (VS) on antiretroviral therapy (ART), abdominal obesity (AO) is associated with neurocognitive impairment (NCI). The likely mechanisms involve visceral adiposity, inflammation, and reductions in insulin-like growth factor type 1 (IGF-1), a neurotrophin. Tesamorelin (Tesa) is a synthetic growth hormone releasing hormone that reduces AO and increases IGF-1, suggesting it may mitigate NCI in VS PWH. Methods: We conducted a randomized clinical trial of immediate versus delayed treatment with Tesa with NCI in PWH. Entry criteria were PWH with VS, NCI (global deficit score [GDS] >0.5 on a comprehensive NC battery), and AO as indexed by elevated waist circumference (WC). Exclusions were other confounding conditions other than HIV accounting for NCI, active substance use disorder, and active malignancy. Participants were randomized 3:2 to receive either immediate or delayed Tesa 2 mg SC for 6 months. The primary outcome was the change in NC performance at 6 months by the published summary regression-based change score (sRCS) method, which corrects for the effects of repeated testing. Results: We enrolled 73 participants who met the entry criteria. Per the study design, 43 were randomized to immediate Tesa and 30 to deferred treatment. The groups were well matched on baseline characteristics as follows: mean (95% CI) baseline GDS 0.939 (0.717, 1.161) in the immediate and 0.861 (0.653, 1.069) in the deferred Tesa arms, p=0.619. Mean WC was 111.0 (108.0, 114.0) cm in the immediate and 110.0 (106.1, 113.8) cm in the deferred Tesa arms, p=0.655. The immediate but not deferred Tesa arm showed improved NC performance, mean (95%CI) 0.155 (0.001, 0.309), p=0.048 in immediate, 0.103 (-0.095, 0.301), p=0.295 in deferred Tesa; but the difference for immediate Tesa compared to no treatment (delayed initiation) was not significant (p = 0.673). The immediate arm showed a higher reduction in WC at 6 months compared to the delayed arm (median difference -2.7 [-4.7, -0.7] cm, p=0.015). Conclusion: These findings indicate that Tesa did not significantly improve NCI in VS PWH with AO compared to delayed initiation, but the study was underpowered to confidently show a relationship. Other limitations were that the study was unblinded and did not include a concomitant placebo arm. These findings do not support the hypothesis that AO contributes significantly to NCI in PWH. Changes in Cognition, Mood, and Sleep Following EFV-DTG Switch in South Africa: The CONNECT study Sam Nightingale 1 , Anna J. Dreyer 1 , Kevin Thomas 1 , Gert U. van Zyl 2 , Eric Decloedt 2 , Pieter Naude 1 , Catherine Orrell 1 , Phumla Sinxadi 1 , Alan Winston 3 , Saye Khoo 4 , John Joska 1 1 University of Cape Town, Cape Town, South Africa, 2 Stellenbosch University, Cape Town, South Africa, 3 Imperial College Healthcare NHS Trust, London, United Kingdom, 4 University of Liverpool, Liverpool, United Kingdom Background: Both efavirenz (EFV) and dolutegravir (DTG) have been associated with neuropsychiatric side effects. Rates of cognitive impairment and CSF escape have not been comprehensively studied in African populations, and the effect of EFV-DTG switch on cerebral function is not known. Methods: 178 virally supressed PWH on EFV-based ART were studied at baseline, and 145 followed up at 1-year following switch to DTG. 95 people without HIV (PWoH) were recruited from the same area, matched for age and sex, and 40 followed up at 1-year. Participants underwent comprehensive cognitive testing over 7 domains, measures of mood (Center for Epidemiologic Studies Depression Scale (CESD)), anxiety (State-Trait Anxiety Inventory) and sleep (Pittsburgh Sleep Quality Index). PWH had cerebrospinal fluid (CSF) sampling for HIV RNA quantification. Global cognition was assessed by T-scores and low cognitive performance by global deficit score ≥0.5. Mixed effects regression models were used to investigate the effects of switch on cerebral function parameters. Results: Global cognitive performance was 2.57 T-score points lower in PWH than PWoH at baseline (p<.001), but was not significantly different between groups at follow-up (figure). Rates of low cognitive performance were higher in

and biological significance of both mICPs and soluble ICPs (sICPs) in the central nervous system (CNS) have not yet been systematically studied. Methods: We used a multiplex immunoassay to simultaneously quantify the concentrations of 16 sICPs in cerebrospinal fluid (CSF) samples from 33 HIV negative individuals (HNIs) and 105 people living with HIV (PLWH), including 80 cases with HIV-associated neurocognitive disorder (HAND) and 25 cases without HAND. We also used immunohistochemistry (IHC) analysis of brain tissues (frontal cortex and hippocampus) from rhesus macaques (RMs) with and without simian immunodeficiency virus (SIV) infection. Results: We found that 10 sICPs (sHVEM, sCD27, sGITR, sICOS, sLAG-3, sPD-1, sTIM-3, sBTLA, sCD28, & sCD40) were consistently detected in all CSF samples, and most of them were highly elevated in PLWH. Strikingly, CSF sHVEM was significantly increased in HAND when compared to PLWH without HAND. These 10 sICPs were also detectable in the CSF samples from RMs. IHC analysis of brain tissues (frontal cortex and hippocampus) from RMs with and without simian immunodeficiency virus (SIV) infection showed that mHVEM was expressed at a basal level on neurons, but not on astrocytes or microglia, and mHVEM expression was highly increased in SIV-infected RMs (SIV/RMs). Conclusion: Our results revealed for the first time that ICPs were altered in the CNS of PLWH, particularly those with HAND. The CSF levels and profiles of sICPs such as sHVEM can potentially be used as a biomarker for HAND severity and progression. Our results will provide insights into the roles of ICPs in the CNS neuroimmune dysregulation and neuroinflammation of PLWH with and without HAND. Immune Checkpoint Signatures Associated With Impaired Cognition in People Living With HIV Ana Joy Lozano 1 , Christian Francisco 1 , Marissa Alejandria 1 , Glen Chew 2 , Chathura Siriwardhana 2 , Nina Gloriani 1 , Louie Mar Gangcuangco 2 , Robert Paul 3 , Cecilia Shikuma 2 , Lishomwa Ndhlovu 4 1 University of the Philippines Manila, Manila, Philippines, 2 University of Hawaii, Honolulu, HI, USA, 3 University of Missouri St Louis, St Louis, MO, USA, 4 Weill Cornell Medicine, New York, NY, USA Background: HIV-associated brain injury (HABI) persists among people with HIV (PWH) despite suppressive antiretroviral therapy (ART). Immune checkpoints (IC) interactions have been associated with HIV comorbidities in PWH on ART and IC blockade has been shown to restore immune function in the field of Oncology. Given the absence of effective interventions for HABI, we assessed for relationships with measures of IC pathways and neurocognitive deficits in PWH on suppressive ART. Methods: A cross sectional study of PWH (n=50) living on stable ART (>12 months) with undetectable plasma HIV RNA (<50 copies/mL) and HIV uninfected (n=50) demographically-matched controls were recruited in Metro Manila, Philippines to participant in the study and provide blood and undergo cognitive assessments. We assessed expression of ICs (PD-1, TIGIT, TIM-3, LAG-3) and their cognate ligands on immune cells using multiparametric flow cytometry. Neuropsychological (NP) performance tests were conducted and assessed for association with ICs and ligand expression. Non-parametric comparisons between the two groups were performed and Spearman's correlations. Results: We observed an expansion of single and multiple ICs on both CD4 and CD8 T cells in PWH compared to HIV-uninfected controls. No differences were observed in cognate ligand expression. Only verbal memory and fine motor performance tests were impaired in PWH compared to controls (p<0.05). Higher PD-1+ CD4 T cell frequencies correlated with better verbal memory (r=0.41, p=0.003) and worse fine motor (r=-0.39, p=0.005) performance, while higher TIGIT+ CD4 T cells correlated with worse verbal memory (r=-0.35, p=0.01) in PWH but not in the control group. Given that neuronal cells have been known to express PD-L1 and PVR, a known TIGIT ligand, we further confirm the expression of PD-L1 and PVR on neuroblastoma cells and assessed the interaction of IC expressing CD4+ T cells with neuroblastoma cells. We observed that PD-1High CD4+ T cells in vitro increased PD-L1 expression on neuroblastoma cells and this was associated with an increase in TNF-α production. PD-L1 blockade reduced neuronal expression of PD-L1 but was insufficient to reverse the inflammatory response. Conclusion: Our findings suggest that interactions of immune checkpoints on T cells with neuronal cells may drive a neuroinflammatory process leading to cognitive deficits in PWH despite viral suppression and additional intervention beyond IC blockade may be necessary.

Poster Abstracts

551

553

CROI 2024 149