CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Univ of California San Diego, La Jolla, CA, USA, 2 Univ of California San Diego, San Diego, CA, USA Background: Sensitive markers of HIV effects on the central nervous system (CNS) are critical to assess the impact of early treatment or CNS reservoir eradication strategies, particularly in those with suppressed viral load (SVL). This pilot study compared performance on a working memory task with varying load (N-back) between young adults with behaviorally acquired HIV (YWH) and uninfected controls and compared brain activity during N-back between YWH and controls using magnetoencephalography (MEG), a functional imaging technique with fine-grained spatial and temporal resolution. Methods: Twelve YWH and 13 age- and education-matched controls, males aged 18-24, completed cognitive testing and structural MRI, and performed an N-back task (0, 1 and 2-back) in the MEG scanner. D-prime was computed as the z-score of the hit rate minus the z-score of the false alarm rate for each N-back condition. MEG data were processed using the Fast-VESTAL source imaging program and activation for control participants was subtracted from that for YWH across frequency bands and cortical areas separately for each condition. MEG analyses used cluster analysis with voxel size>500. N-back and MEG analyses used t-tests with p<0.01. Results: Among YWH, mean CD4 count was 494 and 10 had SVL; mean duration since diagnosis was 36 months. D-prime decreased as working memory load increased, as expected. YWH and controls had comparable 1-back (4.43 and 4.57 for YWH and controls, respectively) and 2-back (2.75 and 2.79) performance but YWH had marginally lower 0-back d-prime (5.39) than controls (6.02). YWH had different patterns of activation during N-back, with both hyperactivation (dlPFC, anterior cingulated/paracingulate gyrus, superior parietal lobe, fusiform and insular cortex across frequency bands, supplementary motor area in beta and gamma) and hypoactivation (bilateral frontal pole across frequencies, and widespread superficial cortical gray in beta and gamma frequencies) compared to controls. Conclusion: YWH showed striking differences in brain activation from uninfected controls during N-back despite only minor differences in performance, suggesting alterations in substrates underlying working memory functioning. MEG may detect subtle functional changes and warrants study as a marker of early CNS impact in relatively recent infection. 404 LEDIPASVIR/SOFOSBUVIR RAISES TENOFOVIR DIPHOSPHATE CONCENTRATIONS IN RED CELLS Christine MacBrayne 1 , Daniel S. Fierer 2 , Kristen M. Marks 3 , Peter L. Anderson 1 , Lane R. Bushman 1 , Kimberly M. Hollabaugh 4 , Michael D. Hughes 4 , Raymond T. Chung 5 , Susanna Naggie 6 , Jennifer J. Kiser 1 1 Univ of Colorado, Aurora, CO, USA, 2 Icahn Sch of Med at Mt Sinai, New York, NY, USA, 3 Weill Cornell Med, New York, NY, USA, 4 Harvard Univ, Boston, MA, USA, 5 MGH, Boston, USA, 6 Duke Univ, Durham, NC, USA Background: ACTG 5327 (“SWIFT-C”) is an ongoing study of sofosbuvir (SOF)-based treatment of acute Hepatitis C virus (HCV) in HIV-infected individuals. We previously reported that participants in Cohort 1 of SWIFT-C taking SOF and ribavirin had 4.3-fold (range 1.4-15.8) higher intracellular tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots (DBS), but there are no data with SOF and the HCV NS5A inhibitor, ledipasvir (LDV). The objective of this analysis was to compare TFV-DP concentrations in red blood cells (RBC) measured with DBS and tenofovir (TFV) concentrations in plasma before, during, and after LDV/SOF treatment in participants in Cohort 2 of SWIFT-C. Methods: Plasma and DBS were obtained from participants taking tenofovir disoproxil fumarate (TDF). TFV-DP was measured in those with available samples at entry, weeks 2 and 8 of LDV/SOF treatment and 2 (EOT+2), 4 (EOT+4), 8 (EOT+8), and 12 weeks (EOT+12) following completion of LDV/SOF treatment. For the 12 participants with data through EOT+12, TFV-DP was also measured at weeks 1 and 4 to provide additional information on the kinetics of the interaction. TFV in plasma was measured at entry, week 8 and EOT+12. TFV and TFV-DP were log transformed for analysis and compared at each visit to study entry using paired t-tests. Results: 19 participants (5 Hispanic, mean±SD age 43.7±8.4yrs, weight 77.4±10.2kg, and CrCl 106.1±24.4 mL/min) were taking a TDF-based antiretroviral (ARV) regimen prior to commencing 8 weeks of LDV/SOF. Geometric mean TFV-DP and TFV concentrations are shown in the table. At weeks 1, 2, 4 and 8 of LDV/SOF treatment, TFV-DP was 7.1, 9.7, 16.7 and 16.6-fold higher in DBS, respectively compared with study entry (all p < 0.001). By EOT + 12, TFV-DP concentrations were similar to baseline (p=0.39). Plasma TFV levels were 1.9 fold higher at week 8 vs. study entry (P=0.0014) and similar between study entry and EOT+12 (P=0.56). Conclusion: After 8 weeks of LDV/SOF treatment, TFV-DP concentrations in DBS were increased 16.6-fold and TFV in plasma was increased 1.9 fold. TFV-DP accumulated rapidly in DBS after starting LDV/SOF (more than doubling within the first week), but declined consistent with the 17-day half-life in RBC after LDV/SOF therapy was completed. This suggests enhanced RBC loading during LDV/SOF therapy. Additional studies are needed to determine the mechanism, magnitude in other cell types, and clinical significance of this interaction.

Poster and Themed Discussion Abstracts

405 TENOFOVIR DIPHOSPHATE ARISING FROM TAF IS QUANTIFIABLE IN DRIED BLOOD SPOTS Jose Castillo-Mancilla , Ryan P. Coyle, Jia-Hua Zheng, Lucas Ellison, Laura Roon, Jordan Fey, Lane Bushman, Jennifer J. Kiser, Peter Anderson Univ of Colorado, Aurora, CO, USA

Background: Tenofovir diphosphate (TFV-DP) in red blood cells measured with dried blood spots (DBS) is a useful marker of cumulative tenofovir disoproxil fumarate (TDF) dosing, given its long half-life of approximately 17 days. However, studies have not assessed TFV-DP in DBS arising from tenofovir alafenamide (TAF). We aimed to determine whether TFV-DP can also be quantified in DBS during TAF therapy. Methods: DBS were obtained from HIV-infected individuals on TAF-based therapy, using convenience sampling at various times post dose. Participants were either TDF-naïve or had been off any TDF-based therapy for at least 5 months. TFV-DP in DBS was measured using a validated LC-MS/MS method. The observed concentrations of TFV-DP in DBS from TAF were compared with the expected concentration of TFV-DP from TDF for daily dosing based on a previously published pharmacokinetic model. Data are presented as median (range). Results: A total of 10 samples from 10 participants (9 White males; 1 Black female) were analyzed. Median age was 40 (26-62) years, and median hematocrit was 46 (41-55) percent. All had HIV-RNA <200 copies/mL. Eight participants were considered to be at steady-state (>8 weeks of therapy) with a median of 14 (9-21) weeks on TAF. The median

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