CROI 2016 Abstract eBook

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women who received monthly DHA-PQ only, an even greater decrease for HIV+ women was found. For all women, mean PQ on Days 14 and 21 were consistently <10 ng/mL, lower than previously estimated for effective chemoprevention (30 ng/mL), and for HIV+ women, Day 7 values were also <10 ng/mL. No significant link between QTc change or QTc at C max with either C max or AUC was found. Conclusions: EFV results in significant reductions in PQ exposure in HIV+ pregnant women as measured by AUC with terminal concentrations persistently lower than previously suggested thresholds. Clinical correlates of these lower levels need to be determined, and dose escalation strategies may merit study.

Table: Pharmacokinetics of PQ in HIV+ and HIV- pregnant women receiving DHA-PQ as chemoprevention

HIV-

HIV+

HIV-

monthly DHA-PQ

monthly DHA-PQ

monthly or bimonthly DHA-PQ

Parameters

GM; 95%CI (n=17) 359 (275, 468) 133 (106, 168) 7.75 (6.14, 9.79) 8.09 (6.40, 10.2) 7.28 (5.43, 9.76) 2.68 (1.93, 3.72) 1.05 (0.579, 1.89)

GM; 95%CI (n=30) 391 (323, 474) 185 (163, 211) 11.4 (9.64, 13.6) 13.0 (11.0, 15.4) 18.3 (14.7, 22.8) 7.00 (5.41, 9.05) 5.09 (4.19, 6.17)

GMR 0.918 0.719* 0.680** 0.622** 0.398*** 0.383*** 0.206***

GM; 95%CI (n=13) 339 (249, 462) 191 (148, 247) 12.8 (10.2, 16.2) 15.0 (12.2, 18.5) 21.8 (14.6, 32.4) 9.44 (6.68, 13.3) 6.43 (4.79, 8.65)

GMR

C max (ng/mL)

1.06

t 1/2

0.696

(hr)

AUC 0-21d

0.605** 0.539** 0.334** 0.284** 0.163***

AUC 0- ×

C 7d

C 14d C 21d

concentra)on;t1/2ishalf-­‐life;C7d,C14d,andC21dareconconday7,14,and21post-­‐1stdoseofa3-­‐dayDHA-­‐PQdose. *p<0.05;**p<0.005;***p<0.0001 GM:geometricmean;CI:confidenceinterval;GMR:geometricmeanra)o(BC2/BC1),AUCunitishr·∙µg/mL;concentra)onunitisng/mL.C max is maximum

102LB Concentrations of TFV and TFVdp in Female Mucosal Tissues After a Single Dose of TAF Katy L. Garrett 1 ; Mackenzie L. Cottrell 1 ; Heather M. Prince 1 ; Craig Sykes 1 ; Amanda Schauer 1 ; Anne Peery 1 ; James Rooney 2 ; Scott McCallister 2 ; Cynthia Gay 1 ; Angela Kashuba 1 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2 Gilead Scis, Inc, Foster City, CA, USA Background: The administration of oral tenofovir disoproxil fumarate (TDF) results in 100-fold higher exposure of tenofovir (TFV) and its active moiety, tenofovir diphosphate (TFVdp), in colorectal tissues compared to female genital tract tissues. This may contribute to PrEP adherence forgiveness in MSM compared to women. Tenofovir alafenamide (TAF), a novel TFV prodrug, achieves higher concentrations of TFVdp in peripheral blood mononuclear cells (PBMCs) compared to TDF. We sought to characterize genital and rectal tissue pharmacokinetics (PK) in women after a single dose of TAF. Methods: A phase I PK study to describe TAF, TFV, and TFVdp exposure over 14 days in blood and tissues was conducted in 8 healthy women given one 25mg dose of TAF. Each participant provided 10 plasma, 9 PBMC, 9 cervicovaginal fluid (CVF) samples, and 2 biopsies from the cervix, vagina, and rectum. TAF, TFV, and TFVdp concentrations were determined by validated LC-MS/MS methods. TAF lower limit of quantification (LLOQ) in plasma was 0.05ng/ml and 0.005ng/ml in tissues. TFVdp LLOQ was 0.02ng/ml in tissues and PBMCs. TFV LLOQ was 0.25ng/ml in plasma and 2ng/ml in CVF. Noncompartmental PK analysis was conducted using WinNonlin v6.4. 48h PK parameters, from an earlier single 300mg dose of TDF in healthy women were used as reference values. Data are reported as median (min-max) except for tissues where pooled sample analysis was used. Results: PK data are listed in the table. In plasma, compared to TDF, the area under the TFV concentration time curve (AUC) 0-48hrs was 95% lower with TAF. By 6h, TAF was mostly unquantifiable in plasma, with an AUC 0-6hrs of 38 (20.5-119.6) ng*h/ml. TAF was undetectable in tissue. Conversely, in PBMCs, TFVdp AUC 0-48hrs was 808% higher with TAF. In all mucosal tissues TFV AUC 0-48hrs was 20-90% lower with TAF. TFVdp was detectable in only 2 vaginal and cervical (12.5%) and 4 rectal (25%) tissue samples of women dosed with TAF, compared to 50%, 100%, and 100% for TDF, respectively. Conclusions: After TAF dosing, plasma TFV PK and PBMC TFVdp PK were consistent with previous reports. Unlike TDF dosing, TFVdp was undetectable in most (83%) tissues after TAF dosing. Although the appropriate biomarkers of HIV protection for PrEP are currently unknown, these biopsy findings warrant further investigation.

Oral Abstracts

103 HPTN 069/ACTG 5305: Phase II Study of Maraviroc-Based Regimens for HIV PrEP in MSM

Roy Gulick 1 ;Timothy J.Wilkin 1 ;Ying Chen 2 ; Raphael J. Landovitz 3 ; K. R. Amico 4 ; AliciaYoung 5 ; Paul Richardson 6 ; Mark A. Marzinke 6 ; Marybeth McCauley 7 ; Kenneth H. Mayer 8 1 Weill Cornell Med Coll, New York, NY, USA; 2 Fred Hutchison Cancer Rsr Cntr, Seattle, WA, USA; 3 David Geffen Sch of Med at Univ of California Los Angeles, Los Angeles, CA, USA; 4 Univ of Michigan Sch of PH, Ann Arbor, MI, USA; 5 SCHARP, Seattle, WA, USA; 6 Johns Hopkins Univ, Baltimore, MD, USA; 7 FHI 360, Washington, DC, USA; 8 The Fenway Inst, Fenway Hlth, Boston, MA, USA Background: Maraviroc (MVC) is an HIV entry inhibitor that concentrates in the genital tract/rectum and can be given orally once-daily, making it a possible alternative PrEP agent.

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CROI 2016