CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

424 CNS TOXICITY OF DTG IS NOT ASSOCIATED WITH PSYCHIATRIC CONDITIONS OR PLASMA EXPOSURE Christian Hoffmann 1 , Eva Wolf 2 , Knud Schewe 1 , Michael Sabranski 1 , Hans- Jurgen Stellbrink 3 , Axel Adam 1 , Thomas Buhk 1 , Stefan Hansen 1 , Stefan Fenske 1 , Thomas Brinkmann 4 , Harald Ertl 4 , Jürgen Hartleb 4 , Gerrit Mohrmann 4 , Christian Noah 4 1 ICH Study Center, Hamburg, Germany, 2 MUC Research, Munich, Germany, 3 Infectiologisches Centrum, Hamburg, Germany, 4 Labor Lademannbogen, Hamburg, Germany Background: Reported rates of neuropsychiatric adverse events (NPAEs) leading to Dolutegravir (DTG) discontinuation in clinical routine have been markedly higher than seen in randomized trials (RCTs), in particular in female and in older pts. It has been speculated that this may be due to higher background rates of psychiatric conditions in HIV+ pts and/or elevated plasma drug levels in specific populations. Methods: In this single center study, charts of all HIV+ pts who had initiated DTG outside RCTs were evaluated for depressive disorders or other neuropsychiatric diagnoses (ICD-10-CM, Diagnosis Codes F01-F99). In addition, DTG plasma levels from frozen samples collected at various time points after drug intake of pts discontinuing DTG due to NPAEs were measured by liquid chromatography coupled with tandemmass spectrometry (LC−MS/MS). Levels were compared with levels of a control group of pts with a comparable age and gender distribution who had continued DTG containing regimens for at least one year without reported neuropsychiatric problems. Results: In total, 861 pts (768 males, median age 47.1 years) had initiated DTG outside RCTs since 2014, among them 151 treatment-naïve and 710 treatment- experienced pts. There were 155 pts (18.0%) with depressive disorders and 55 pts (6.4%) with other neuropsychiatric diagnoses. After a median follow-up of 19.6 months, 54/861 pts (6.3%) had discontinued DTG due to NPAEs, mainly sleep disorders (74%), dizzyness (52%), and paraesthesia (33%). NPAEs leading to discontinuation were observed more frequently in women (hazard ratio [HR] 2.31; 95% confidence interval [CI] 1.12-4.74, p=0.03), in patients older than 60 years (HR 2.14; 95% CI 1.10-4.18, p=0.025), but not in patients with depressive disorders (HR 1.00; 95% CI 0.54-1.88, p=0.952) or other neuropsychiatric diagnoses (HR 0.93; 95% CI 0.29-3.00, p=0.896). In 37 patients who had discontinued DTG due to NPAEs of whom stored samples were available, population plasma drug levels of DTG including peak levels did not differ substantially from control pts who did not discontinue DTG due to NPAEs. Conclusion: In this large cohort of HIV+ patients exposed to DTG in clinical routine, discontinuation due to NPAEs was around 6 %. Drug discontinuation was not associated with a pre-existing or prevalent depression or with other neuropsychiatric diagnoses, but with female sex and older age. The effect of DTG plasma exposure on the occurrence of NPAEs appears to be limited. 425 BRAIN VOLUMES CHANGES AFTER ABC/3TC + EFV OR TDF/FTC + ATV/R AS FIRST-LINE ART Ignacio Pérez-Valero 1 , Lucia Bailon 1 , Alicia Gonzalez 1 , Belen Alejos 1 , Helena Melero 2 , Norberto Malpica 2 , Jose I. Bernardino 1 , Juan González-García 1 , Jose R. Arribas 1 1 Hospital La Paz Institute for Health Research, Madrid, Spain, 2 Universidad Rey Juan Carlos, Madrid, Spain Background: Volumetric MRI studies evaluating the effect of ART initiation over cortical and subcortical grey matter (GM) volume changes are scarce, non- randomized and don’t compare the effect of ART regimens with different CNS penetration (CP) and neurotoxicity (NT) profiles. Methods: Randomized, open-label, 24-week pilot clinical trial comparing brain structures (3T-MRI) and neurocognitive changes (NC) in 7 domains after ART initiation with arm1: ABC/3TC+EFV (higher CP and in vitro NT) vs. arm 2: TDF/FTC+ATV/r (lower CP and in vitro NT). We compared volume and thickness changes (week 24 – day 0), in patients who completed all study procedures both by intention to treat (ITT: all patients) and per protocol (PP: excluding patients who changed therapy or did not achieve virologic suppression) analysis. Volumes were calculated using Freesurfer software and normalized using the Intracranial Volume and the Mean Thickness. Comparison were performed using the Wilcoxon signed-rank test and a linear regression estimative model adjusted by significant baseline covariables. Volume changes and NC changes were correlated using Pearson’s r. Results: 25 Caucasian (91.7%) male (100%), mean age: 37.3 years, median CD4+: 480 cells and recent HIV diagnosis (mean time: 0.6 years) were included.

24 of them completed all study procedures (13 allocated to arm 1 and 11 to arm 2). No baseline differences were observed between study groups. During the study, 1 patient (arm 1) discontinued due to a non-related SAE (pneumonia) and 2 had to change therapy (EFV and ATV-related toxicities). By week 24, 10 of 12 patients on arm 1 and 9 of 10 on arm 2 achieved virologic suppression on randomized ART. At week 24, changes in total GM and cortical volumes were different between study arms, by ITT and PP (table). These volumes tended to increase in arm 2 and to decrease in arm 1. No differences were detected in subcortical GM or in cortical white matter volumes. Decrease in total cortical volume correlated (p<0.05) with lower scores in processing speed (WAIS III - Symbols Search: r=0.41), motor functioning (Grooved - Dominant Hand: r=0.48) and verbal fluency (COWAT - PMR: r=0.43). Conclusion: Our results suggest that the type of ART selected as initial therapy might have a role preserving the grey matter and the cortical integrity. The regimen with lower CP including drugs with lower in-vitro NT tended to preserve grey matter cortical integrity than the comparator with higher CP and higher in vitro NT. Confirmatory studies are needed.

Poster Abstracts

426 LONGITUDINAL PET IMAGING OF THE SEROTONERGIC SYSTEM IN SIV- INFECTED NONHUMAN PRIMATES Swati Shah 1 , Sanhita Sinharay 1 , Dianne Lee 1 , William C. Reid 1 , Paul Wakim 1 , Kenta Matsuda 2 , Avindra Nath 1 , Vanessa Hirsch 2 , Michele Di Mascio 2 , Dima A. Hammoud 1 1 NIH, Bethesda, MD, USA, 2 NIAID, Bethesda, MD, USA Background: Despite known increased depression rates in HIV+ patients compared to controls, there is limited literature evaluating the underlying mechanisms of depression in HIV. A previous 11 C-DASB (DASB) PET study (serotonin transporter (SERT) ligand) showed higher binding in depressed compared to non-depressed HIV+ patients, potentially reflecting serotonergic dysfunction as a component of HIV-associated neuropathology. In this study we wanted to assess longitudinal changes in SERT expression in SIV-infected macaques using 11 C-DASB PET imaging before and after inoculation, to better understand the pathophysiology of HIV-associated depression. Methods: Seven Rhesus macaques were infected with a neurovirulent SIV strain (SIVsm804E) known to cause SIV encephalitis in approximately 80% of animals with the Q/Q TRIM5α genotype. Baseline and multiple post inoculation (P.I) follow-up DASB PET scans were obtained using a High Resolution Research Tomograph head-only camera. Correlation of DASB binding potentials (BP ND ) with CSF cytokines, CSF and plasma viral loads (VL) as well as duration of infection was performed. Preliminary qPCR was used to assess the expression of SERT mRNA in frontal lobe tissues of 2 infected animals and 2 controls. Results: Out of the 7 animals, four animals progressed quickly (average 6.5 weeks P.I.) and had to be rescued with treatment. One animal had to be euthanized 12 weeks P.I. Two animals progressed very slowly and did not show symptoms until 90 weeks P.I. Treatment was eventually discontinued in 4 animals and they were allowed to progress to a chronic infectious stage. Six out of 7 macaques showed higher BP ND in the midbrain (range 7-72%, mean=28.31%) at the last time point compared to baseline (fig.1A, B). Neither treatment initiation nor interruption had an effect on BP ND . A repeated-measures mixed model analysis showed that only disease duration was associated with DASB BP ND (p= 0.04). qPCR showed higher SERT mRNA expression in two infected macaques compared to two uninfected animals (fig.1C).

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