CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Poster and Themed Discussion Abstracts

381 CENICRIVIROC IMPROVES NEUROCOGNITION AND REDUCES MONOCYTE ACTIVATION IN TREATED HIV Lishomwa C. Ndhlovu 1 , Michelle L. D’Antoni 1 , Robert Paul 2 , Kalpana J. Kallianpur 1 , Laurent Fischer 3 , Eric Lefebvre 3 , Star Seyedkazemi 3 , Beau K. Nakamoto 1 , Debra Ogata-Arakaki 1 , Cecilia Shikuma 1 1 Univ of Hawaii, Honolulu, HI, USA, 2 Univ of Missouri–St. Louis, St. Louis, MO, USA, 3 Tobira Therapeutics, Inc, South San Francisco, CA, USA Background: Our current understanding of the pathogenesis of HIV-associated neurocognitive impairment (NCI) centers on the migration of activated inflammatory monocytes (MO) into the central nervous system (CNS). We hypothesized that antagonizing CCR2 and CCR5 will improve NCI by decreasing MO activation and transmigration. Methods: A single arm, 24-week, antiretroviral (ART) intensification trial of cenicriviroc (CVC, a dual CCR2 and CCR5 antagonist) in HIV-infected subjects on stable ART>1 year with plasma HIV RNA <50 copies/ml. CVC, a CYP3A4 and P-gp substrate, was dosed based on co-administered ART. Neuropsychological (NP) performance included measures of psychomotor speed (PM), executive function (EF), learning and memory (LM), and working memory (WM). Domain-specific standardized scores (NPZ) were determined and a global NPZ was defined by aggregating the domain scores. At enrollment, subjects were classified as either having low cognitive performance if the NPZ for one or more domains was -0.5 or lower (n=11). All others were classified as cognitively normal (n=6). Plasma markers of monocyte activation (neopterin, soluble (s)CD14 and sCD163) were measured by ELISA. Wilcoxon signed rank test and Pearson correlations were performed for nonparametric and parametric analyses, respectively. Results: Seventeen subjects, 94%male, median age 55 [IQR 47, 58], and median CD4 count, 545 [404, 731] were included. Significant 24-week improvements in NPZ_global (median change 0.255; p=0.017) and NPZ_WM (median change 0.44; p=0.015) were observed independent of baseline cognitive status. Improvements in NPZ_LM (median change 0.07; p=0.430), NPZ_EF (median change 0.23; p=0.207) and NPZ_PM (median change 0.33; p=0.0797) after 24 weeks were not significant. Significant 24-week decreases were observed for sCD163 (median change -1.54ng/ml; p=0.001), sCD14 (median change -1.17ng/ml; p=0.003) and neopterin (median change -0.87ng/ml; p=0.0004). A 24-week decrease in neopterin predicted an increase from entry to week-24 in NPZ_WM (r=-0.52; p=0.03). Separate analyses in subjects with low vs normal cognitive performance at baseline did not show any appreciable differences in results. Conclusion: Intensification of ART with CVC may lead to an improvement in NCI, which is associated with a reduction in monocyte immune activation in virally suppressed subjects with chronic HIV. Further study of CVC in a randomized controlled study is warranted. 382 CSF INFLAMMATORY MARKERS AFTER ADDING MARAVIROC TO MONOTHERAPY DARUNAVIR/RITONAVIR Tristan Barber 1 , Arkaitz Imaz 2 , Marta Boffito 1 , Daniel Podzamczer 2 , Anton Pozniak 1 , Rosa Fortuny 2 , Nicholas Davies 1 , Jordi Niubo 2 , Sundhiya Mandalia 3 , Brian Gazzard 1 1 Chelsea and Westminster NHS Fndn Trust, London, UK, 2 Hosp Univ de Bellvitge, Barcelona, Spain, 3 Imperial Coll London, London, UK Background: Alternative ART strategies such as protease inhibitor monotherapy have raised concerns about CNS penetration. CINAMMON is a phase IV, open-label, single-arm, pilot study to assess the role of maraviroc (MVC) addition to darunavir/ritonavir monotherapy (mono-DRV/r) in virologically suppressed patients. Methods: Subjects on mono-DRV/r with VL<40 in London and Barcelona were recruited if showing a CCR5 tropic results and remained on mono-DRV/r for 12w before adding MVC. Lumbar puncture (LP) and neurocognitive (NC) function (Cogstate) examinations were performed at baseline, w12 and following 24w of MVC (w36). CSF and plasma DRV/r concentrations were measured at w12 and w36, and MVC at w36. The primary study endpoint was week (w) 12 to w36 CSF inflammatory markers changes (neopterin, S100b, neurofilament heavy chain (NFH), CSF ferritin) following MVC 150mg qd addition to mono-DRV/r 800/100mg qd for 24w. Secondary endpoints included changes in neurocognitive function (Cogstate), and CSF drug levels, following addition of MVC. Results: Nineteen patients were recruited and 15 completed the study (17M, 2F). Drop outs were for headache (2), knee problemmeaning could not attend (1), and personal reasons (1). Mean age (range) was 45.4 years (27.2-65.1), 13/19 were white and 10/19 MSM. No changes in S100b, NfH, CSF ferritin, neopterin were seen between w12 and w36. Overall NC function improved between w12 and w36 following MVC addition: total age adjusted z score improved by 0.27 (weighted paired t-test; p=0.11). Looking at tests for executive function only, in this group age adjusted z score improved by 0.54 (weighted paired t-test; p=0.03). This compared to tests for other (non-executive) cognitive function where the age adjusted z score showed no significant change between w12 and w36 (weighted paired t-test; p=0.25). Darunavir plasma:CSF concentration ratio did not change between w12 (132) and w36 (112; p=0.577, Wilcoxon signed rank). Maraviroc plasma:CSF concentration ratio was 35 at w36.

CROI 2017 153