CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: 29 of 30 women completed the study (15 TDF, 14 placebo). The mean age was 29.7 years. There were 43 adverse events; 8 were product related & were Grade 1. Median TFV vaginal fluid (VF) levels in 10 women at 1, 3, 7 & 14 d after VR insertion were 4, 5, 7 & 7.3 x 10 4 ng/mL, respectively. Only 1 had detectable TFV-DP by DBS after 7 d but 11 of 14 had detectable levels after 14 d of TDF VR use (range 37-335 fmol/punch). Tissue TFV-DP levels in 10 women ranged from 52-550 fmol/mg. Tissue fromwomen in TDF arm challenged ex vivo had a 90% reduction in HIV copy number compared to no change in the placebo arm (p<0.0001, Mann Whitney). Compared to baseline, cervical swab eluants significantly inhibited HIV replication at 7 (p=0.002) & 14 d (p=0.01, Wilcoxon matched-pairs signed rank test) after VR use in TDF group, which correlated significantly with cervical swab TFV levels (r=0.52, p=0.01, Spearman correlation). Tissue TFV-DP levels were greater after VR use than those observed after oral TDF in the highly effective Partners PrEP trial, but less than levels achieved after TFV gel dosing (Table).

Conclusions: A TDF VR is safe, well tolerated & resulted in TFV VF levels that exceed the clinical correlate of protection observed with TFV gel BAT24 dosing. TFV-DP detected in DBS suggests that it may provide a sensitive maker of adherence. Findings support further development of this TDF VR.

993 Investigating the Pharmacokinetics of Rectal 1% Tenofovir Gel in Rhesus Macaques Charles W. Dobard 1 ; AndrewTaylor 1 ; Chuong Dinh 1 ; Chou-Pong Pau 1 ; Ian McGowan 2 ; Lisa Rohan 2 ;Walid Heneine 1 1 Centers for Disease Control and Prevention, Atlanta, GA, USA, Atlanta, GA, US; 2 University of Pittsburgh Magee-Womens Research Institute, Pittsburgh, PA, US

Background: Rectally formulated gels containing antiretroviral (ARV) drugs are under development to prevent rectal HIV transmission. Efficacy of ARV gels will likely depend on efficient drug release and absorption through the rectal mucosa. However, little is known on how gel volumes and physiological barriers such as feces and mucus may affect drug absorption. This study evaluated pharmacokinetics of different volumes of 1% TFV gel in a macaque model and investigated the effect of feces and mucus on systemic drug absorption. Methods: 1% TFV was formulated in a rectal specific hydrogel based formulation. The formulation was designed to have neutral pH (7) and be close to iso-osmolar (479 ± 6 mOsmol/kg). The effect of gel volume on systemic TFV absorption was investigated in macaques (n=6) receiving 4, 1, and 0.5 mL of 1% TFV gel. Gel application was followed by measurements of plasma TFV levels at 0.5, 2, 6, and 24 hours by HPLC MS/MS. The Cmax and area under the curve (AUC) values were measured over 24h. The impact of feces and mucus on drug absorption was evaluated by comparing Cmax and AUC values among macaques (n=6) that underwent extensive rectal washes with saline (5 total washes) and unwashed animals (n=6) prior to receiving 4 ml of rectal gel. In all macaques, fecal presence prior to gel dosing, was monitored using pre-moistened rectal swabs. Results: Peak plasma TFV levels were detected at 30 minutes with all gel volumes. In contrast, AUCs and C max values increased proportionally with gel volume. With 4 ml of gel, Cmax and AUC values were 42 ng/ml and 121 ng*h/ml, respectively. These values decreased to10 ng/ml and 37 ng*h/ml with the 1 ml dose, and to 3.8 ng/ml and 7.5 ng*h/ml/h with the 0.5 ml dose. A dose response analysis showed that 1 ml of gel recapitulates systemic TFV levels seen with 4 ml of 1% TFV gel applied rectally in humans (Cmax= 8 ng/ml and AUC=52 ng*h/ml/h). Rectal washes significantly increased systemic TFV absorption compared to unwashed (AUC 0-24h = 120.15 and 50.25 ng*h/mL, respectively; p=0.01). Conclusions: In this macaque model, dose proportionality was observed between the lowest and highest gel volume of this TFV rectal gel formulation and included a dose that recapitulates the in vivo release and systemic TFV absorption achieved in humans. The higher TFV absorption seen following rectal washes reflects increased mucosal exposure and suggests that cleansing practices prior to gel application may increase TFV exposure in humans. 994 CHARM-01, a Phase 1 Rectal Safety, Acceptability, PK/PD Study of 3 Tenofovir Gels Ian McGowan 1 ; Kathy Duffill 2 ; Charlene Dezzutti 1 ; Nicola Richardson-Harman 3 ; Mark A. Marzinke 4 ; Ross D. Cranston 1 ; Lisa Rohan 1 ; CraigW. Hendrix 4 ; Julie Elliott 5 ; Peter Anton 5 1 University of Pittsburgh, Pittsburgh, PA, US; 2 Magee-Womens Research Institute, Pittsburgh, PA, US; 3 Alpha StatConsult LLC, Damascus, MD, US; 4 Johns Hopkins University School of Medicine, Baltimore, MD, US; 5 David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, US Background: Three formulations of tenofovir (TFV) gel have been evaluated in clinical trials and it is uncertain which gel formulation should be developed as a rectal microbicide. The CHARM-01 study was undertaken to characterize the rectal safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three TFV gels: a vaginal formulation (VF), a reduced glycerin vaginal formulation (RGVF), and a rectal formulation (RF) with osmolalities of 3111, 846, and 479 mOsmol/kg respectively. The VF gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials. The VF gel was used in the RMP-02/MTN-006 Phase 1 rectal safety study. The RGVF gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. Methods: Participants received 4 mL of the three TFV gels in a blinded, crossover design and received in a randomized sequence: (i) 6 daily doses of a HEC placebo followed by a final single dose of the VF gel, (ii) 7 daily doses of the RGVF gel, and (iii) 7 daily doses of the RF gel. Safety, acceptability, compartmental PK, and explant PDwere monitored throughout the trial. Results: A total of thirteen participants were enrolled into the CHARM-01 study at two sites in Los Angeles and Pittsburgh. All three gels were found to be safe and acceptable. Median rectal tissue homogenate TFV-diphosphate (DP) concentration was significantly greater with the RF (10.3 ng/mg) versus the VF (below the limit of quantification) gel (p ≤ 0.05). Median mucosal mononuclear cell (MMC) TFV-DP was significantly greater with the RF (1136 fmol/10 6 cells) versus RGVF (320 fmol/10 6 cells) gel (p ≤ 0.05). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal explant HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV diphosphate (DP), MMC TFV-DP (Figure 1), rectal fluid TFV, and explant HIV-1 infection.

Poster Abstracts

Figure 1: Pharmacokinetic / Pharmacodynamic relationship betweenmucosal mononuclear cell concentrations ofTFV-DP and colorectal explant supernatant HIV-1 p24 levels (overall P < 0.0001)

586

CROI 2015