CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Univ of Colorado Denver, Aurora, CO, USA, 2 San Francisco Dept of Pub Hlth, San Francisco, CA, USA Background: Tenofovir-diphosphate (TFV-DP) in red blood cells measured with DBS is a useful marker of cumulative tenofovir disoproxil fumarate (TDF) adherence, given its ~17 day half-life. To date, adherence interpretations were based on pharmacokinetic (pk) modeling from 17 individuals who received 30 days of daily TDF/emtricitabine (FTC). DOT-DBS prospectively evaluated TFV-DP pk at steady-state, dose-proportionality, and comparability with earlier pk modeling. Methods: HIV negative subjects were recruited from Denver and San Francisco (SF). Subjects were randomized to 2 of 3 TDF/FTC doses (as a % of daily dosing) for 12 wks each; 100%, 67%, and 33%, separated by a 12-wk washout. Arms 33% and 67%were balanced by; “intermittent” (skipping days) and “holiday” (skipping wks). Doses were observed in person or by live video. DBS fromwk 12 were analyzed. Demonstration that TFV-DP was directly proportional with cumulative dosing (dose proportionality) required the 90% CI for slope of ln dose on wk 12 ln TFV-DP to be within 0.80-1.20. Mixed models were used. Subgroup analyses were univariate. Results: 48 adults were included, 24 from each site; 23 males, 26 white, 8 black, 14 Hispanic (2 black). Median (range) age was 29 (21-49) years, weight 77 (51-155) kg, CrCl 98 (69-156) ml/min, HCT 43% (35-49). Two subjects completed only the 1st dosing period and two were within 4 wks of finishing the 2nd. TFV-DP was dose-proportional; slope 1.02 (90% CI 0.94-1.09). Table shows results for each dose. Sub-group analyses showed no statistical differences in dose proportionality. TFV-DP did not vary substantially by “Intermittent” vs “holiday”, CrCl, or HCT. SF and blacks trended towards lower TFV-DP compared with Denver and whites, -12% (95% CI, -24, 0.4) and -14% (-27, 2.3), respectively. TFV-DP was 22% (7, 39) higher in females than males. Study estimates were comparable with the earlier pk model, which assumed dose proportionality and used rounded 25th percentiles for 28.6%, 57.1%, and 100% dosing (2, 4, 7 doses/wk); results were 355 vs 350, 719 vs 700, and 1271 vs 1250 fmol/punch, respectively. Conclusion: TFV-DP in DBS was dose proportional and estimates matched a previous pk model used for adherence interpretations. Some variability may be explained by SF (sea level) vs Denver (5280 feet), blacks vs whites and females vs males. These differences should be explored further. TFV-DP in DBS provides an estimate of cumulative dosing that can be used to interpret average adherence to TDF-based therapy. 420 IN VITRO AND IN VIVO EVALUATION OF BIODEGRADABLE IMPLANT CONTAINING TAF FOR HIV PREP Phillip G. Durham 1 , Greg Gatto 1 , Leah Johnson 1 , Mark A. Marzinke 2 , Stephanie Swarner 1 , Ginger Rothrock 1 , Tejal Desai 3 , Ian McGowan 4 , Ida Washington 5 , Ariane van der Straten 6 1 RTI Intl, Durham, NC, USA, 2 The Johns Hopkins Univ, Baltimore, MD, USA, 3 Univ of California San Francisco, San Francisco, CA, USA, 4 Univ of Pittsburgh, Pittsburgh, PA, 5 Magee-Womens Rsr Inst, Pittsburgh, PA, USA, 6 RTI Intl, San Francisco, CA, USA Background: Subcutaneous implants for Pre-exposure prophylaxis (PrEP) could provide constant protection from HIV over several months. Polycaprolactone (PCL) is used as a biodegradable thin film for membrane controlled, zero-order drug release kinetics from implantable devices. We assessed in vitro and in vivo release of Tenofovir (TFV) (2:1 ratio). Three TAF dosing groups targeted to deliver 0.98, 0.49 and 0.1 mg/day for 30 days (high [H], medium [M] and low dose [L], respectively) were fabricated by scaling device size and surface area. In vitro, 6 devices/group were evaluated (PBS, 37°C) and TAF release was measured at 2-day intervals by UV visible spectroscopy. Six rabbits/group were implanted with a single device. We collected blood samples (days 0-45) and peripheral blood mononuclear cells (PBMCs; days 21-45). Devices were retrieved from all animals for further analysis. Drug and metabolite concentrations were determined via liquid chromatographic-tandemmass spectrometric analysis. Here we report plasma TFV and TAF concentrations (ng/ml) and PBMC TFV diphosphate (TFVdp) concentrations (fmol/10 6 cells). Results: In vitro TAF devices showed linear release (R 2 >0.95) for a mean of 17.4 days (H group) and 21 days (M and L groups). The average release of TAF was proportional to the device sizes over 15.92 days, with observed releases 24%-47% faster than targeted. In the H group, plasma TAF was quantifiable for ≤ 21 days, TFV for ≤ 30 days, and PBMC TFVdp at 21-day only (Table 1). TAF release in vitro highly correlated (R 2 >0.98) to both TAF and TFV levels in vivo as determined by the average in vitro release rate for each group at 15.92 days and TAF and TFV plasma concentrations at 14 days. Conclusion: Devices showed dose dependent sustained plasma TAF and TFV levels that correlated with in vitro release of TAF. In vitro data suggests in vivo depletion occurred between days 14-21, coincident with the disappearance of TAF from plasma. After depletion, TAF, TFV and TFVdp levels quickly reduced to below quantification. This short end-of-dose resolution may avoid long sub-effective drug PK tail. Using the in vitro/in vivo correlation as a reference, additional experiments are planned to evaluate the PK of maximally loaded devices to release TAF for a much longer duration. Alafenamide Fumarate (TAF) from PCL devices, to demonstrate sustained levels of TAF and its metabolites in rabbits. Methods: PCL films (25 μm) were solvent-cast, formed into an open-end hollow rod and loaded with TAF and PEG 300

Poster and Themed Discussion Abstracts

421LB HPTN 076: TMC278 LA SAFE, TOLERABLE, AND ACCEPTABLE FOR HIV PREEXPOSURE PROPHYLAXIS Linda-Gail Bekker 1 , Shuying S. Li 2 , Betsy Tolley 3 , Mark A. Marzinke 4 , Nyaradzo Mgodi 5 , Jessica E. Justman 6 , Shobha Swaminathan 7 , Adeola Adeyeye 8 , Jennifer H. Farrior 3 , Nirupama Sista 3 1 Univ of Cape Town, Cape Town, South Africa, 2 FRCHC, Seattle, WA, USA, 3 FHI 360, Durham, NC, USA, 4 Johns Hopkins Univ, Baltimore, MD, USA, 5 Univ of Zimbabwe, Harare, Zimbabwe, 6 ICAP at Columbia Univ, New York, NY, USA, 7 Rutgers Univ, Newark, NJ, USA, 8 NIH, Rockville, MD, USA Background: Adherence to daily pre-exposure prophylaxis (PrEP) is difficult for many people so finding alternative strategies is a priority. HPTN 076 evaluated safety and acceptability of the long-acting injectable form of rilpivirine (TMC278 LA) for PrEP. Methods: HPTN 076 is a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg TMC278 LA (LA) to placebo (P). Injectable product was administered to low risk, sexually active HIV-uninfected women in two gluteal, intramuscular (IM) injections every eight weeks over a 48-week period. Injections followed 28-days of self-administered daily oral rilpivirine (RPV, 25mg). Acceptability, safety and pharmacokinetic data were collected throughout the study. Product was paused for any participant with Grade (Gr) ≥2 related or Gr ≥3 unrelated adverse events (AEs). Results: A total of 136 (100 African, 36 US) women were enrolled; median age 31 years (IQR: 25,38), median weight 75kg (IQR: 64, 89), 46%married, 94% Black and 60% unemployed. Ten women withdrew (8 RPV, 2 P) and four had product discontinued (3 RPV, 1 P) during the oral phase (Weeks 0-4). A total of 122 (80 LA, 42 P) women received ≥ one injection; 98 (64 LA, 34 P) received all six injections. During the injection phase (Weeks 4-52), one woman withdrew (P) and 16 product discontinuations (10 LA, 6 P) occurred.

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