CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

378

DIFFERENTIAL IN VITRO NEUROTOXICITY OF ANTIRETROVIRAL DRUGS Cagla Akay-Espinoza , Anna L. Stern, Rebecca l. Nara, Nina Panvelker, Jiean Li, Kelly L. Jordan-Sciutto Univ of Pennsylvania, Philadelphia, PA, USA

Background: Mounting evidence suggests antiretroviral drugs (ARVs) may potentially contribute to the persistence and evolution of clinical and pathologic presentation of HIV- associated neurocognitive disorders (HAND), which impacts 30%–50% of HIV+ patients in the post-antiretroviral (ART) era. We previously reported that two first generation HIV protease inhibitors (PIs), ritonavir and saquinavir, led to oxidative stress and induced the unfolded protein response (UPR), with subsequent synaptic damage and neuronal death in vitro. Intriguingly, augmentation of the endogenous antioxidant response (EAR) by monomethyl fumarate (MMF) reversed PI-induced neurotoxicity. In this study, we determined whether two newer PIs, darunavir and lopinavir, were deleterious to neurons in vitro. Further, we expanded our assessment to include two integrase inhibitor (IIs) class ARVs, dolutegravir and elvitegravir. Methods: Primary rat neuroglial cultures at 14−21 days in vitro were treated with increasing therapeutically relevant doses of ARVs for 4 h–8 days, and oxidative stress, mitochondrial membrane potential, UPR activation and neuronal viability were assessed. Results: Within the II class, elvitegravir but not DTG was neurotoxic in a dose dependent manner after 2, 4, and 8 days of treatment. Within the PI class, lopinavir but not darunavir was neurotoxic after 2d. Moreover, lopinavir increased BiP, a UPR marker, and heme-oxygenase 1 (HO-1), an EAR protein induced in response to oxidative stress, whereas mitochondrial membrane potential was decreased with lopinavir treatment. Preliminary results indicated that two HO-1 inducers, MMF and 1-(2-Cyano-3,12,28-trioxooleana- 1,9(11)-dien-28-yl)-1H-imidazole (CDDO-Im), partially ameliorated lopinavir-induced neurotoxicity. Conclusion: These findings support our previous observations that PI-induced neurotoxicity could be alleviated by EAR induction. Intriguingly, ARV-mediated deleterious effects were observed with certain PIs and IIs, providing support for the potential class- and drug-specific neurotoxic effects of ARVs. Future in vivo studies are needed to confirm the neurotoxicity profiles of ARVs for potential incorporation into patient management. Furthermore, the EAR may be a potential access point for the development of adjunctive therapies to complement ART to limit their contribution to HAND persistence. 379 DISCORDANT HIV RNA IN OLFACTORY MUCOSA OF HIV-POSITIVE PATIENTS Andrea Calcagno 1 , Tiziano Allice 2 , Luca Bertero 1 , Mattia Trunfio 1 , Maria Enrica Amasio 3 , Daniele Imperiale 3 , Valeria Ghisetti 2 , Giovanni Di Perri 1 , Paola Cassoni 1 , Stefano Bonora 1 1 Univ of Torino, Torino, Italy, 2 Ospedale Amedeo di Savoia, Torino, Italy, 3 Ospedale Maria Vittoria, Torino, Italy Background: Central nervous system (CNS) HIV infection may have relevant long-term consequences for HIV-positive patients. Compartmental viral suppression is tested on cerebrospinal fluid (CSF) samples, although the latter might represent a surrogate marker of brain tissue. The olfactory mucosa (OM) is the only CNS tissue that is easily accessible and its collection may represent a non-invasive diagnostic technique. Methods: Treated and untreated HIV-positive patients undergoing a lumbar puncture for clinical reasons were included. After signing a written informed consent, patients underwent (<72 hours from the spinal tap) a nasal brushing: after local epinephrine application, 4 swabs (Copan diagnostics) were consequently inserted (2 for each nostril) and a 360-degree rotation performed. Swabs were either inserted in 4% formaldehyde (stained with monoclonal anti-olfactory marker protein, OMP, clone B-6, Santa Cruz Biotechnology, Inc.) or in Copan UTM viral transport medium. Plasma and CSF HIV RNA were quantified with CAP/CTM v.2.0 HIV-1 (Roche Molecular, USA, detection limit 20 copies/ mL). HIV RNA was measured in OM (1mL) with a modified CAP/CTM procedure. Data are expressed as medians (interquartile ranges). Results: 19 patients were included (52.6%male, 68.4% Caucasian, 63.2% on treatment): median age was 49 years (43-58). Median CD4+ T lymphocytes were 174 cells/uL (30- 375). Plasma and CSF HIV RNA were 5.2 Log10 copies/mL (4.9-5.7) and 2.2 Log10 copies/mL (1.3-3) in untreated and <1.3 Log10 copies/mL (<1.3-1.8) and <1.3 Log10 copies/mL (<1.3-1.7) in treated subjects; CSF escape was observed in 3 patients (15.8%). Patients’ diagnoses included HAND (9 patients, 5 asymptomatic and 4 mild neurocognitive disorders), late-presentation (5), or other conditions. Mild discomfort and sneezing were the only reported side effects. All samples showed a high cellularity, anti-OMP intensity and a median of 45% (30-72) anti-OMP positive cells. OM HIV RNA was detectable in 10 samples [2.43 Log10 copies/mL (1.97-3.21] and it showed a significant correlation with plasma (rho=0.67, p=0.001), but not CSF HIV RNA (rho=0.26, p=0.273). Conclusion: Nasal brushing is a safe and promising procedure that allows a non-invasive collection of olfactory mucosa cells, including olfactory neurons. HIV RNA can be measured in most samples and it correlated with plasma viral load: studies are ongoing to understand the clinical relevance and source of this mucosal HIV RNA. 380 CAN WE AFFORD TO WAIT? ART AND THE CNS Kevin Robertson 1 , Javier R. Lama 2 , Christopher D. Pilcher 3 , Jessica Rios 2 , Peter Brandes 2 , Eduardo Ruiz 2 , Eline Appelmans 4 , Serena Spudich 5 , Ann Duerr 4 , for the SABESTeam 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 Asociacion Civil Impacta Salud y Educacion, Lima, Peru, 3 Univ of California San Francisco, San Francisco, CA, USA, 4 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA, 5 Yale Univ, New Haven, CT, USA Background: The central nervous system (CNS) is an early target of HIV infection and inflammation. The prevailing belief is that early identification and treatment are crucial to preventing HIV-associated cognitive impairment. However, the optimal timing of antiretroviral therapy (ART) initiation required to prevent these neurological outcomes remains unknown. Methods: The SABES study followed high-risk HIV- MSM and transgender women (TW) with monthly HIV testing (serology and RNA). We enrolled MSM/TWwith acute (seronegative but HIV RNA+) and recent (seropositive with negative HIV RNA test within past 3 months) HIV infection. Participants were randomized to initiate ART (FTC/TDF/EFV and FTC/TDF/COBI/EVG) immediately after diagnosis or 24 weeks later. They underwent a neurocognitive assessment of 8 functional domains. Results: Participants with acute HIV (N=31: 16 immediate arm; 15 deferred arm) and recent HIV (N=57: 26 immediate arm; 31 deferred arm) underwent assessments at baseline (N= 31 assessments in immediate arm & 57 in deferred arm), week 12 (N=30 & 57), week 24 (N=27 & 53), and week 48 (N=23 & 34). Participant demographics at enrollment were mean age 26.8 years, education 12.4 years, CD4+ cell count 463 and HIV RNA 5.68 log cps/ml. Overall neurocognitive (total z) and domain scores were derived from site-specific normative data (positive scores reflect better performance). Overall, there was significant improvement over time in total z score among participants (F(3,188)= 27.15, p<.0001), reflecting the positive effects of entrance to care, practice/learning and ART initiation. There was a trend for greater neurocognitive improvement among participants in the immediate arm at the 48 week time point (F(1,46)=2.84, p=.09) (See Fig. 1). Conclusion: This unique randomized cohort offers a rigorous assessment of the consequences that delays in ART initiation may have on neurocognitive function. These preliminary results suggest that HIV care that includes ART initiation very shortly after HIV acquisition resulted in greater improvement in participants’ neurocognitive performance over time. Long term follow-up of these participants will provide valuable insights on the further evolution of these early differences in neurocognitive functioning.

Poster and Themed Discussion Abstracts

CROI 2017 152