CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

443 Cerebrospinal Fluid Markers in Long-Term Atazanavir/Ritonavir Monotherapy Francesca Ferretti ; Alba Bigoloni;Valeria Longo; Laura Galli; Laura Passeri; Simonetta Gerevini;Vincenzo Spagnuolo; Adriano Lazzarin; Paola Cinque; Antonella Castagna San Raffaele Scientific Institute, Milan, Italy Background: Central nervous system (CNS) viral escape is a concern in ritonavir boosted protease inhibitors monotherapy. Aimwas to assess viral escape and immuneactivation marker levels in the cerebrospinal fluid (CSF) of patients on successful long-term atazanavir/ritonavir (ATV/r) monotherapy. Methods: MODAt (NCT01511809) is a multicentric, randomized, open-label, non-inferiority trial. Patients on ATV/r 300/100mg+2 N(t)RTIs since ≥ 48 weeks, virologically suppressed since ≥ 24 weeks, were randomized to ATV/r-monotherapy (arm A) or to maintain ATV/r+2N(t)RTIs (arm B). In this sub-study, paired CSF and plasma samples were collected in patients with plasma HIV-RNA viral load <50 c/mL at ≥ 96 study weeks, including those with early re-intensification for confirmed viral failure, considered in arm B, after evaluation with brain magnetic resonance imaging (MRI) to assess HIV-RNA and immuneactivation markers soluble CD14 (sCD14) and CD163 (sCD163), CCL2, CXCL10 and interleukin-6 (IL-6) by ELISA. Results are expressed as median (interquartile range). Variables were compared with Wilcoxon rank sum or Fisher exact test, as appropriate; Spearman test was applied to assess correlations. Results: We evaluated 23 patients (Arm A=11, Arm B=12): 95%males, 43 years old (38-47), with nadir CD4+ cells 334/ m L (268-366), pre-treatment HIV-RNA 4.86 log10 c/mL (4.49-5.43), no previous AIDS diagnosis, CD4+ at randomization of 599 cells/ m L (467-699) and undetectable plasma VL since 19.5 months (13.7-48.7). At CSF evaluation, after 120 (108-132) weeks, all patients were neuroasymptomatic, had no pathological MRI findings and CD4+ 679 (443-925) cells/ m L (similar between the two arms, p=0.705). CSF HIV-RNA was detected in no patients on triple therapy and in one on monotherapy (study week 120, nadir CD4+ of 311 cells/ μ L, two HIV-RNA blips of 94 and 99 c/mL during the study), who was re-intensified. CSF biomarker levels did not differ between the two arms. CSF cell number (normal range ≤ 1 cell/ μ L) was slightly higher in the monotherapy arm (Table). Overall, CSF IL-6 was significantly correlated with plasma IL-6 (r=0.70, p<0.001) and CSF sCD14 with plasma sCD14 (r=0.49, p=0.016).

Conclusions: CSF escape was uncommon in asymptomatic patients on long-term, successful ATV/r monotherapy. CSF immune activation was not substantially different between patients on ATV/r monotherapy compared to triple therapy. 444 Neurocognitive Decline Is AssociatedWith Antiretroviral Concentrations in Plasma and Cerebrospinal Fluid (CSF) Qing Ma 1 ; Xia Liu 2 ; Robert Heaton 1 ; Fujie Zhang 2 ; Hua Jin 1 ; HaoWu 2 ; Melanie Crescini 1 ; Hongxin Zhao 2 ; Hui Zeng 2 ; Scott Letendre 1 1 University of California San Diego, San Diego, CA, US; 2 Chinese Center for Disease Control and Prevention, Beijing, China Background: Therapeutic antiretroviral therapy (ART) drug concentrations in the central nervous system (CNS) are likely important for controlling HIV replication in the brain although their relationship to neurocognitive impairment (NCI) remains controversial. The objective was to investigate associations between drug concentrations with incident NCI in a randomized clinical trial comparing two ART regimens, tenofovir-lamivudine-efavirenz (TDF-3TC-EFV, T3E) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP, Z3N), in China. Methods: A total of 23 HIV+ adults were evaluated in a nested case-control substudy: 11 who developed NCI (decliners) after 48 weeks of ART and 12 who did not (non-decliners). Cases and controls were matched by sex, education, ethnicity, and baseline NC performance, but not treatment regimen. Plasma and CSF were sampled at a median of 12.4 hours post-dose and drug concentrations were measured by LC/MS/MS. Results: Subjects were all Han Chinese men with a mean age of 32.9 years. All subjects had plasma HIV RNA levels below 50 c/mL. Similar to the findings of the parent trial (presented in a separate abstract), decliners were more frequently randomized to T3E (58.3% vs. 36.4%, RR 1.53). Decliners had markedly higher plasma TDF concentrations (d=2.2, p=0.004) and lower TDF CSF-to-Plasma Ratios (CPRs, d=1.3, p=0.028) than non-decliners with a trend towards higher EFV CPRs (d=1.0, p=0.09). Recursive partitioning identified that none of the 5 subjects who had plasma TDF concentrations < 33.5 ng/mL were decliners while all 6 subjects who had plasma TDF concentrations ≥ 33.5 ng/mL and EFV CPRs ≥ 0.46%were (p=0.0004). Conclusions: In this small, nested case-control study, incident NCI was associated with TDF and EFV drug concentrations. The observed association with low TDF CPRs may reflect suboptimal antiviral efficacy in the CNS while the association with high EFV CPRs may reflect neurotoxicity. Together, the observed CPR associations may indicate disturbances in the permeability and drug transport properties of the blood-brain barrier that predispose to development of HIV-associated NCI. 445 Viral Decay Rate in the Cerebrospinal Fluid After Initiating Antiretroviral Therapy Natalie M. Bowman 1 ; Sarah B. Joseph; Prema Menezes 1 ; Jessica Margolis 1 ; Christopher Lippincott 1 ; Michael J.Vinikoor 1 ; Kevin R. Robertson 1 ; Richard Price 2 ; Ronald Swanstrom 1 ; Joseph Eron 1 1 University of North Carolina, Chapel Hill, NC, US; 2 University of California San Francisco (UCSF), San Francisco, CA, US Background: Initiation of antiretroviral therapy (ART) typically results in the rapid decay of HIV-1 in the cerebrospinal fluid (CSF); however, in a subset of HIV-infected people, virus in the CSF decays very slowly despite the use of ART. We examined factors that predict the rate of viral decay in the CSF after initiating ART. Methods: We recruited treatment-naïve patients with CD4 < 400 starting antiretroviral therapy (ART). All participants underwent medical and neurological examination, neuropsychiatric testing, blood draw, and lumbar puncture (LP) at baseline and 2-4 weeks after initiation of ART. We measured blood and CSF HIV viral loads (VL), CD4 count, and

Poster Abstracts

309

CROI 2015