CROI 2016 Abstract eBook

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Poster Abstracts

Results: TZM-bl assay results showed RPV has an ED 99 , 100 µM of RPV added to the cultures was needed to fully inhibit HIV infection in ectocervical tissue, while 10 µM was needed to inhibit HIV infection in colonic tissue. RPV added to the basolateral mediumwas more effective with 10 µM and 1 µM protecting ectocervical and colonic tissues, respectively. Improved activity was likely due to a longer pre-incubation with basolateral drug. To better estimate the amount needed for protection, RPV was quantified from ectocervical and colonic explant tissues treated basolaterally and significant inverse linear correlations (P < 0.001) with culture p24 were obtained. An Emax model showed RPV concentrations of >273 nM in ectocervical and >27.3 nM in colonic tissues were associated with HIV inhibition. Conclusions: Our data show that RPV can suppress HIV infection in mucosal tissue, but higher levels of RPV are needed in female genital tissue than gastrointestinal tissue for protection. Based on our findings, rectal tissue RPV concentrations reached in clinical trials appears to be sufficient to block HIV infection, but at least 2-fold more drug is needed in female genital tissue to demonstrate similar inhibition. These data suggest targeted use of RPV for HIV prevention may be warranted of 8.27 nM and a CD 99 of 492 nM against HIV-1 BaL . When applied to the apical surface at the same time as HIV-1 BaL

875 A First-in-Human Trial of PC-1005 (MIV-150 and Zinc Acetate in a Carrageenan Gel) Barbara A. Friedland 1 ; Craig Hoesley 2 ; Marlena Gehret Plagianos 1 ; Shimin Zhang 1 ; Elena Hoskin 1 ; Mohcine Alami 1 ; NataliaTeleshova 1 ;Thomas Zydowsky 1 ; José Fernández-Romero 1 ; George Creasy 1 1 Pop Council, New York, NY, USA; 2 Univ of Alabama at Birmingham, Birmingham, AL, USA Background: Pre-clinical data show PC-1005 to be potent against HIV, HSV-2 and HPV when applied vaginally or rectally. Primary objectives of this study were to assess the safety and pharmacokinetics (PK) of PC-1005 (comprised of the NNRTI MIV-150 and zinc acetate [ZA] in a carrageenan [CG] gel). Acceptability, adherence, and pharmacodynamics were also explored. Methods: 20 healthy, abstinent women participated in a placebo-controlled, double-blind Phase 1 trial (RCT) at 1 US site, and were randomized (4:1) to apply 4 mL of PC-1005 or placebo vaginally once daily for 14d. The RCT was preceded by an open label safety run-in (OL) with 5 women applying PC-1005 once daily for 3d. Assessments included physical and pelvic exams, PK blood draws, safety labs, and colposcopy (with biopsies and cervicovaginal lavages [CVL] in the RCT). MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and CG (CVL) concentrations were measured with LCMS-MS, ICP-MS, and ELISA, respectively. Antiviral activity against HIV, HSV-2 and HPV in CVL was measured using cell-based assays. Adherence and acceptability were assessed quantitatively via paper-based questionnaires. Safety, acceptability and adherence data were analyzed descriptively. PK parameters were calculated using non-compartmental techniques and actual sampling times. EC 50 values for CVL antiviral activity were calculated using a dose-response inhibition analysis. Results: All 5 participants completed the OL period and applied 3/3 doses. 17 participants completed the RCT, 2 were lost to follow up (1 never dosed), 1 withdrew before dosing, and 16 applied ≥ 93% of doses. Participants were 30 years old, on average (range 19-44) and 52%were Black or African American. Acceptability was high; 94% of participants reported willingness to use the gel in the future. AE rates, most of which were mild and/or unrelated, were similar in both gel groups. MIV-150 was absorbed systemically at low levels without accumulation (Table 1). Plasma zinc concentrations were unchanged from baseline. 7/7 CVLs collected 4h post-dose demonstrated measurable anti-HIV and anti-HPV activity. High antiviral activity in baseline CVLs precluded assessment of anti-HSV-2 activity in cell-based assays. Conclusions: PC-1005 gel used vaginally for 14d was well-tolerated, with low systemic absorption of MIV-150, and measurable HIV and HPV antiviral activity in CVL. These results warrant continued development of PC-1005 as a viable vaginal or rectal microbicide for prevention of HIV and other STIs.

Poster Abstracts

368

CROI 2016