CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Of the 25 subjects with intensive PK data: 21 were male (84%) and 21 non-cirrhotic (4 cirrhotic). Median age (range) was 49.2 (21.2-64.0) years, weight was 65.5 (46.2-88.3) kg and body mass index 23.3 (18.3-30.9) kg/ m2. Median RDV AUC0-24h, Cmax and C24 were 17.3 (3.2-69.9) µg.hr/mL, 2.3 (0.4-6.4) µg/mL and 0.11 (0.03-1.63) µg/mL, respectively. Sixty-five HIV/HCV co-infected subjects were included: median age (range) was 42.9 (23.4-61.5) years and weight 62.0 (45.0-100) kg. Tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), efavirenz (EFV) and nevirapine (NVP) were the most commonly prescribed ARVs in HIV/HCV co-infected patients. A total of 47 subjects had tenofovir (TFV) ARVs concentrations before and after SOF/RDV treatment, 34 had FTC, 51 had EFV and 7 had NVP. Mid-dose tenofovir (TFV) concentrations were significantly higher with concomitant SOF/RDV treatment, while mid-dose FTC, EFV and trough NVP concentrations were not significantly different (Table). Conclusion: SOF/RDV had no significant impact on FTC, EFV and NVP concentrations. TFV concentrations were slightly higher with SOF/RDV use but the magnitude is likely not clinically significant. The intensive PK data will aid the development of a population PK model to evaluate the impact of ARVs on RDV exposure. 472 MAPPING THE DISTRIBUTION OF EFAVIRENZ WITH BRAIN TISSUE CELLS Nithya Srinivas 1 , Elias Rosen 1 , Gabriela D. Cruz 1 , Craig Sykes 1 , Amanda Schauer 1 , Lourdes Adamson 2 , Paul Luciw 2 , Angela Kashuba 1 1 University of North Carolina Chapel Hill, Chapel Hill, NC, USA, 2 University of California Davis, Davis, CA, USA Background: Despite ongoing antiretroviral (ARV) therapy, HIV continues to persist in the central nervous system (CNS), as demonstrated by the establishment of latent microglia reservoirs and HIV-associated neurocognitive disorder. HIV persistence in the brain may be due to inadequate drug exposure in HIV-target cells; however, there is little information on brain distribution of ARVs. In this study, we have quantified the concentration of 4 ARVs in brain tissue by LC-MS/MS and infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) while mapping their distribution relative to expression of CD4+ T-cells and CD11b+microglia. Methods: In 4 male macaques (2 uninfected; 2 SHIV-infected) dosed to steady-state, concentrations of 4 ARVs – tenofovir (TFV), emtricitabine (FTC), efavirenz (EFV), and raltegravir (RAL) were measured in 10-micron cerebellum tissue slices by LC-MS/MS (LLOQ of homogenate ranged from 0.002-0.01 ng/mL). IR-MALDESI mass spectrometry imaging (MSI) was used to characterize drug distribution. Density of 1.06g/cm 3 was used to convert tissue concentrations to ng/g. Immunohistochemistry (IHC) staining of CD11b+microglia and CD4+ T-cells was performed on contiguous slices. Image analysis of co-registered MSI and down-sampled IHC images was performed in MATLAB. Results: TFV, FTC, and RAL were not detected by MALDESI and were <100 ng/g by LC-MS/MS (range of concentration was 9.4-61.2 ng/g). EFV concentrations by IR-MALDESI had a standard deviation of 663 ng/g for all samples and was 2.2-fold greater in SHIV- than SHIV+ brain (median = 1596 and 723 ng/g, respectively). The fractional coverage of target cells co-localized with EFV (FrC) differed based on infection status: for CD11b FrC = 22-59% (SHIV+) and 76-81% (SHIV-) and for CD4 FrC = 14-59% (SHIV+) and 73-77% (SHIV-). However, the FrC of total CD11b and CD4 cells exposed to EFV concentrations above IC50 (0.5 ng/g) was considerably smaller: 0-3.3%, regardless of infection status (Figure 1, panel IV). Conclusion: EFV accumulation was 12 to 60-fold greater in brain tissue compared to other ARVs in SHIV+ animals but only 14% to 59% of CD11b and CD4 brain cells in these animals were colocalized with detectable EFV. This suggests that ARV coverage may be incomplete for cell populations that harbor, or can become infected, with HIV. We have shown in this preliminary analysis that this approach has the potential to provide ARV concentration-effect relationships in the brain at the cellular level.

473 SWITCHING TO TAF IN EVG-BASED REGIMENS: CSF PHARMACOKINETICS AND ANTIVIRAL ACTIVITY Qing Ma 1 , Andrew Ocque 1 , Gene D. Morse 1 , Chelsea Sanders 2 , Alina Burgi 2 , Susan J. Little 3 , Scott L. Letendre 3 1 University at Buffalo, Buffalo, NY, USA, 2 University of California San Diego, San Diego, CA, USA, 3 University of California San Diego, La Jolla, CA, USA Background: Tenofovir alafenamide (TAF) co-formulated with elvitegravir (E), cobicistat (C) and emtricitabine (F) has become a recommended regimen, replacing E/C/F/TDF due to improved renal and bone safety. Limited data are available on TAF and EVG pharmacokinetics (PK) in CSF, particularly after switching from TDF. This study aims to measure TAF, EVG, and tenofovir (TFV) concentrations in CSF and compare them to HIV RNA in CSF and neurocognitive (NC) performance. Methods: This was a single-arm, open-label, single-center study. After an initial assessment, 9 participants switched from E/C/F/TDF to E/C/F/TAF and were followed for 24 weeks. At week 0 and week 24, blood was collected at 2, 4, and 6 hours after an observed dose and CSF was then collected within 1 hour of the 6-hour blood collection. Total plasma and CSF concentrations were determined by LC/MS-MS. The wild-type HIV-1 IC50 for EVG was 3.9 ng/ml. HIV RNA was measured in plasma and CSF by RT-PCR (lower limit of quantitation, LLQ, 20 copies/mL). NC performance was estimated by the Montreal Cognitive Assessment (MoCA) with a score <26 indicating impairment. Adherence was determined by pill count. Changes in drug concentrations between visits were analyzed using paired, two-sided signed rank tests. All concentrations are expressed in ng/ml. Results: EVG concentrations in CSF remained stable (p=0.203) while EVG concentrations in plasma increased over time (p=0.004, see table). TFV concentrations in both CSF (p=0.004) and plasma (p=0.004) declined over time. The CSF:plasma ratio (CPR) for EVG remained stable over time (p=0.359) while the TFV CPR increased (p=0.004). At 24 weeks, TAF concentrations in plasma peaked 2 hours after the dose [11.05 (2.84-147.11)] but below LLQ at 6 h. TAF was not detected in CSF at 6 h. All HIV RNA levels remained ≤ 40 copies/mL in CSF and plasma. The proportion of EVG concentrations in CSF exceeding the IC50 rose from 56% at week 0 to 88% at week 24, although this difference was not statistically significant (p=0.375). Four participants (29%) had NC impairment at week 0 and 2 (14%) remained impaired at week 24. Across both assessments, higher EVG CPR values (but not TFV CPR) correlated with better NC performance (r=0.426, p=0.078). Conclusion: Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF, and substantially lower TFV concentrations in plasma, but stable EVG concentrations in CSF and plasma. No virological failure or significant NC changes were detected at 24 weeks following switch.

Poster Abstracts

CROI 2018 169