CROI 2016 Abstract eBook

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Poster Abstracts

Methods: Therapy naïve, neurologically asymptomatic, HIV-positive patients were randomly allocated on a 1:1 basis to a standard boosted-protease-inhibitor (bPI) ART regimen (Arm1; tenofovir-emtricitabine plus atazanavir/r) or a maraviroc 150mg once daily intensified bPI regimen (Arm2: abacavir-lamivudine plus darunavir/r/maraviroc). A detailed assessment of 11 cognitive function (CF) tests was undertaken at baseline and after 12, 24, 36 and 48 weeks and cerebral metabolites measured using proton magnetic resonance spectroscopy in the right frontal white matter (FWM) at baseline. Mean and proportional changes in CF, changes in individual domains between treatment arms and factors associated with changes in CF were assessed. Results: Of 60 subjects randomised (30 Arm1 and 30 Arm2), 58 were male and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4+ count 425 (246) and 434 (229) cells/uL and plasma HIV RNA (IQR) 44K (16 to 69K) and 53K (27 to 81K) copies/mL in arms1 and 2, respectively. At week 48 plasma HIV RNA was <200 copies/mL in all and mean (SD) CD4+ count was 586 (209) and 611 (249) cells/uL in arms1 and 2, respectively. CF improved over 48 weeks (mean change z-score 0.19 Arm1 and 0.24 Arm2, figure). No statistically significant differences in changes in individual domains or overall CF were observed between study treatment arms however proportional change in overall CF from baseline was numerically greater in arm1. In a multivariate model, greater improvements in overall CF was associated with greater baseline CF performance (coef 0.82, p<0.005) and higher FWM neuronal metabolites (n-acetly aspartate/creatine ratio, coef 0.51, p<0.05). Conclusions: Maraviroc-intensified ART had no demonstrable benefit on CF. In subjects with higher baseline cerebral function markers (higher CF performance and neuronal metabolites), greater improvements in CF was observed. We hypothesise a greater reversibility of underlying disease processes may occur in such individuals.

424LB Neurocognitive Safety After 96-WKs on ATV/r+3TC: Results of the Randomized SALT Trial Ignacio Perez-Valero 1 ; Juan Pasquau 2 ; Rafael Rubio 3 ; Antonio Rivero 4 ; Jesús Santos 5 ; Jose Sanz 6 ; Ana Mariño 7 ; Herminia Esteban 8 ; Jose Antonio Perez-Molina 9 ; for the SALT Study Group 1 Hosp Universitario La Paz, Madrid, Spain; 2 Hosp Virgen de las Nieves, Complejo Hospario Universitario Granada, Granada, Spain; 3 Hosp Universitario Doce de Octubre, Madrid, Spain; 4 Hosp Universitario Reina Sofía, Córdoba, Spain; 5 Hosp Universitario Virgen de la Victoria, Malaga, Spain; 6 Hosp Universitario Principe de Asturias, Madrid, Spain; 7 Hosp Arquitecto Marcide, Ferrol, Spain; 8 Fundación SEIMC-GESIDA, Madrid, Spain; 9 Hosp Universitario Ramón y Cajal, Madrid, Spain Background: Due to its low CNS penetrance, there are concerns about the capacity of non-conventional ART to preserve neurocognitive performance (NP). Methods: The SALT study is a multicentre, open-label, non-inferiority clinical trial that compares whether 3TC+ATV/r (dual therapy; DT) is non-inferior to 2NRTI+ATV/r (triple therapy; TT), in HIV+ patients on a stable 3-drug regimen. The SALT NP sub-study (per protocol analysis) was performed to evaluate the effects over NP of DT vs. standard TT. A global deficit score (GDS) of 5 neurocognitive tasks selected following AAN-2007 criteria were used to assess NP at baseline (BL), W48 and W96. Changes in the neurocognitive impairment rates (NI) (GDS >0.5) and NP (GDS value) were determined at W48 and W96. The effect of DT over GDS at W96 adjusted by GDS at BL, GDS at W48 and significant confounders that change the relation between DT and GDS at W96 >20%was determined using ANCOVA. Results: Per protocol analysis included 92 participants (DT: 47 vs. TT 45). All BL characteristics were comparable in both groups, including mean [95% CI] GDS change: DT 1.2 [0.9 – 1.5] vs. TT 1.1 [0.8 – 1.5]; p=0.80) and rate of NI (DT 66% vs. TT 62.2%; 0.71). At W48 and W96, GDS changes (W48: DT -0.3 [-0.5 to -0.1] vs. TT -0,2 [-0.4 to 0.0]; p=0.39. W96: DT -0.3 [-0.5 to -0.1] vs. TT -0.2 [-0.4 to -0.1]; p=0.471) and rates of NI (W48: DT 55.3% vs. TT 51.1; p=0.69. W96: DT 51.1% vs. TT 51.1%; p=0.99) were similar. This absence of differences was also observed in all cognitive tasks. At W96, two participants in each group developed NI (incidence rate: DT 12.5% vs. TT 11.8%; p=0.95). DT use did not impact NP change: GDS at W96 adjusted by BL and W48 GDS and significant confounders (none) was -0.26 [-0.39 to -0.12] on DT vs. -0.27 [-0.41 to – 0.13] on TT (p=0.90). Conclusions: Neucognitive performance remained stable after 96 weeks both in ATV/r+3TC arm as in the 2NRTI+ATV/r arm provided HIV-suppression was maintained. In this trial, ATV/r + 3TC showed a safe neurocognitive profile through 96 weeks. 425 HIV-1 Maturation Inhibitor BMS-955176: Pharmacokinetic and Exposure-Response Analysis Heather Sevinsky 1 ; Palanikumar Ravindran 1 ; Dirk Schuermann 2 ; BlisseVakkalagadda 1 ; Carey Hwang 1 ; Dara Hawthorne 1 ; Hong Xiao 1 ; Neelanjana Ray 1 ; Max Lataillade 3 ;Timothy Eley 1 1 Bristol-Myers Squibb, Princeton, NJ, USA; 2 Charité Rsr Organisation GmbH, Berlin, Germany; 3 Bristol-Myers Squibb, Wallingford, CT, USA Background: BMS-955176 is a second-generation HIV-1 maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage event between capsid protein p24 and spacer peptide-1, resulting in the production of immature, non-infectious virions. In a proof-of-concept (POC) study, 10 days of BMS-955176 monotherapy led to maximummedian declines in HIV-1 RNA that plateaued at ~1.64 log 10 c/mL at doses of 40–120mg once daily (QD). BMS-955176 showed similar antiviral activity in subjects with either wild-type HIV-1 or HIV-1 with Gag polymorphisms and in subjects with either HIV-1 subtype B or subtype C. Exposure-response (ER) analyses were performed to guide dose selection for further development. Methods: AI468002 (NCT01803074) was a Phase 2a, randomized, multipart trial. In Part A, 60 HIV-1, subtype B-infected subjects (HIV-1 RNA ≥5000c/mL; CD4+ T-cell counts ≥200cells/µL) received an oral suspension of BMS-955176 (5, 10, 20, 40, 80 and 120 mg doses) or placebo (8:2 for each dose group) QD for 10 days. Blood samples for noncompartmental PK analysis were collected on Days 1 and 10, and trough samples on Days 2, 4, 6, and 8. Dose proportionality was assessed using a power model. Blood samples for HIV-1 RNA were collected on Days 1–14, 17, 19 and 24. The ER relationship was assessed using a non-linear, three-parameter sigmoid E max equation, Y = E 0 +E max *C/ (EC 50 +C). Results: Following multiple dose administration of BMS-955176 under fasted conditions, BMS-955176 systemic exposures (C max , AUC TAU and C 24 ) increased ~2-fold from first dose (Day 1) to last dose (Day 10). Day 10 BMS-955176 exposures increased in a generally dose-proportional manner at 5–40mg QD, but were less than dose proportional at 40–120mg QD. Steady state was achieved by Day 6. The ER relationship between Day 10 BMS-955176 C 24 and response (maximum decline in HIV-1 RNA from baseline) (Figure) was described by

Poster Abstracts

161

CROI 2016