CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

concentration of TFV-DP in DBS was 224 (83-254) fmol/punch in these individuals. Two participants were pre-steady-state with 16 days of therapy and their values were 54 and 93 fmol/punch, consistent with a long half-life. Of the samples analyzed at expected steady-state, 7 were obtained from individuals taking co-formulated emtricitabine/cobicistat/ elvitegravir/10 mg TAF; median TFV-DP was 231 (83-254) fmol/punch. One sample was from an individual taking emtricitabine/25mg TAF; TFV-DP was 216 fmol/punch. All participants had detectable concentrations of FTC-TP in DBS, reflecting recent dosing within the last 48 hours. TFV-DP values arising from TAF therapy were lower than from daily TDF dosing (median 1560 fmol/punch). Conclusion: TFV-DP arising from TAF-based therapy is quantifiable in DBS, although at lower levels compared with TDF. TAF does not appear to load red blood cells with tenofovir to the same extent as peripheral blood mononuclear cells. Nevertheless, TFV-DP in DBS appears to be promising for use as a measure of cumulative dosing and adherence to TAF- based therapy. A directly observed therapy study is now underway to evaluate the pharmacokinetics and dose proportionality of TFV-DP arising from TAF. 406 EXTRA/INTRA-CELLULAR NUCLEOSIDE/TIDE SEMEN PHARMACOLOGY: IMPLICATIONS FOR ERADICATION Julie B. Dumond , Stephen A. Greene, Heather M. Asher Prince, Jingxian Chen, Brian Maas, Craig Sykes, Amanda Schauer, Cynthia L. Gay, Angela Kashuba, Myron S. Cohen Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: The male genital tract (MGT) is a putative HIV reservoir and potential barrier to cure. Tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine (FTC) are widely-used NRTIs. Seminal mononuclear cell (SMC) concentrations (C) of TDF, TAF, and FTC may inform effective dosing regimens for HIV cure. Methods: 8 HIV+, 8 HIV- men receiving TDF/FTC and 4 HIV+men receiving TAF/FTC for clinical care provided 6 blood (BP) and seminal plasma (SP) samples to construct a composite 24hr C curve. TFV diphosphate (TFVdp), FTC triphosphate (FTCtp), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP) were measured in peripheral blood mononuclear cells (PBMC) and SMC; SMC for 12 men were pooled due to low cell counts. For PBMC/SMC C below the limit of quantification (LOQ), ½ of the sample LOQ was imputed. Noncompartmental analysis (Phoenix Win Nonlinv6.3, Certara) generated BP and SP area under the curves (AUC) for SP:BP ratios. C over 24h (C ss,ave ) was computed for each analyte. Data are reported as median (IQR). Results: Age, BMI for the HIV+men was 40 (34, 47) yrs and 28.5 (25.8, 32.9) kg/m 2 . Age, BMI for the HIV- men was 30.5 (24, 39) yrs and 28.3 (23.9, 32.1) kg/m 2 . All had eGFR >50 mL/min. HIV+ TDF men had 39% higher SP C than HIV- TDF men. TAF C were also detected for longer post-dose in SP (12h) than in BP (6h), although they were 80% lower than in BP. TFV SP:BP AUC ratios after TDF dosing were 1.6 (0.8,4.7) [HIV+] and 1.1 (0.8, 2.4) [HIV-]; and 9.4 (7.7, 12) after TAF dosing. C ss,ave are in the table. Despite low TFV C in BP with TAF, TFV SP C were similar to SP C in HIV- TDF men. As expected, TFVdp PBMC C with TAF were 4-fold higher than with TDF. SMC TFVdp C were 94% higher with TAF than with TDF. FTC SP:BP ratios were ≥3; FTC SP C in HIV+men were 30-60% higher than HIV- men; FTCtp SMC C were 8-fold higher with TAF. Small changes in median dATP and dCTP SMC C between groups were seen. Conclusion: High TFV C in SP after TAF dosing was unexpected. Cathepsin A in the MGT and differing drug transporter affinities for TAF and TFV may explain these findings. Increased SMC TFVdp C after TAF dosing may reflect both high TFV penetration and increased PBMC C; these data suggest TAF’s MGT distribution differs from TDF. Differing SP/SMC C between HIV+/HIV- men and TFV dosage form suggest drug and disease-specific mechanisms of MGT penetration.

Poster and Themed Discussion Abstracts

407 INTEGRASE AND PROTEASE INHIBITOR CONCENTRATIONS IN LYMPHOID VS GI TISSUES Sulggi Lee 1 , Hiroyu Hatano 1 , Angela Kashuba 2 , Mackenzie L. Cottrell 2 , Teri Liegler 1 , Sophie Stephenson 1 , Ma Somsouk 1 , Peter W. Hunt 1 , Steven G. Deeks 1 , Radojka M. Savic 1 1 Univ of California San Francisco, San Francisco, CA, USA, 2 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: The majority of persistently HIV-infected cells in patients on suppressive antiretroviral therapy (ART) are in lymphoid tissue. Limited drug uptake by lymphoid tissues may contribute to sustained viral persistence. Identifying tissue sources with differential drug uptake may help guide future HIV eradication strategies. Methods: We measured plasma, gut mucosa, and peripheral lymph node drug concentrations from HIV-infected participants with plasma HIV RNA<40 copies/mL for ≥12 months on integrase (raltegravir, RAL) or protease inhibitor (daranavir, DRV, or atazanavir, ATV)-based regimens. Tissue samples were collected in duplicate, homogenized, and quantified using a validated liquid chromatography-mass spectrometry assay. We developed compartmental plasma-tissue PK models used nonlinear mixed effects modeling incorporating previously reported PK parameters for these drugs. Monte Carlo simulations were performed to estimate plasma and tissue PK profiles, and reported IC95 (RAL) or IC90 (DRV, ATV) values were used to calculate Ctrough:IC95/90 ratios. Results: Rectal biopsies were collected from 19 participants (8 RAL, 7 DRV, 4 ATV), with a subset with ileal (2 RAL, 1 DRV, 1 ATV) and lymph node (2 RAL, 1 DRV) samples. The median age was 44 years and median duration of ART suppression was 4.4 years. Tissue:plasma concentration ratios (TPRs) were higher in ileum vs. rectum for RAL and ATV (Table 1A). Median Ctrough:IC95/90 ratios for RAL, DRV, and ATV were: 97.9, 1622, and 2.67, respectively (Table 1B), corresponding to a predicted 100% of RAL and DRV and 80% of ATV participants with rectal concentrations >IC95/90. Adequate lymph node samples were only available for RAL (1 DRV participant demonstrated evidence of nonadherence). Among RAL participants, median Ctrough:IC95 ratios for rectum, ileum, and lymph node were 97.9, 99.9, and 3.20, suggesting lower drug penetration in lymphoid vs. gut tissues. Based on this model, we predict ~15% of patients will have lymph node concentrations<=”” div=””>

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