CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

conditions were maintained by regularly replacing the media. Relationships between release rate and device parameters were evaluated using devices with 10-30µm thick membranes and 50-320 mm 2 surface areas. TAF chemical stability in the TFPD reservoir was evaluated by RP-HPLC. Results: Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at < 2.8mg/day. To achieve membrane controlled release, TAF required additional formulation excipients such as PEG300 or hydroxypropyl-ß-cyclodextrin. The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5-4.4 mg/ day in devices no larger than a contraceptive implant. A proportional relationship between membrane area and release rate was demonstrated. An inverse relationship between membrane thickness and release rate was observed for membranes between 10-15µm, with no further impact on release for membranes > 15µm. Prototype devices demonstrated linear release at 1.2mg/day for up to 90 days and at 2.2mg/day for up to 60 days. We achieved reproducibility in device design and performance with < 10% variability between replicate devices (Figure 1). TAF remained chemically stable in the device reservoir with < 3% change in purity at 50 days Conclusions: We developed a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a > 8-fold range. This system is being further evaluated in vivo .

880 Assessing Formulations of Tenofovir 1% Gel in HIV Seronegative Adults via RNA-Seq Mark Cameron 1 ; AarthiTalla 1 ; PeterWilkinson 1 ; John Pyles 1 ; Rafick Sekaly 1 ; Ian McGowan 2 1 Case Western Reserve Univ, Cleveland, OH, USA; 2 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA

Background: Clinical trials employing rectal microbicides containing antiretroviral drugs have the goal of reducing risk of contracting HIV during sexual activity. The Combination HIV Antiretroviral Rectal Microbicide (CHARM)-01 study is a recent Phase 1, double-blinded, randomized, safety & acceptability, and pharmacokinetic study of rectally-applied tenofovir-based microbicides in healthy adults (aged 37.7 years ± 14.3) completed by the Microbicide Trials Network (MTN). With the hypothesis that gene expression changes in the local immune environment may hallmark the action of tenofovir and potentially alter risk of HIV infection, we used RNA-Seq to assess changes in the rectal mucosa caused by gel usage. Methods: Three tenofovir 1% gel formulations were administered rectally: a vaginal formulation (VF, 3111 mOsmol/kg), a reduced-glycerin vaginal formulation (RGVF, 846 mOsmol/kg), and a rectal-specific formulation (RF, 479 mOsmol/kg). Participants received 4 mL of the gels: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. We isolated total RNA from rectal biopsies from participants (n=14/group) and performed low input Illumina Truseq RNA-Seq on a HiSeq 2500 instrument. Top ranking differentially expressed genes by P value (P<0.05 in T or F tests) were forwarded to Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis. Results: Multi Dimensional Scaling analysis of the top 500 genes by F-Test P value showed that RGVF had the most significantly different (P=0.001, Kruskal Wallis rank sum test) expression profile from baseline. RGVF increased T cell related proinflammatory responses (IFNG, IL12, CXCL9/10), complement (C2, CASPs), antiviral interferons (OAS1, IFIs/IFITs, MX1), and IL10. This signature was unique to RGVF, however a derivative signature of up- and down-regulated IFNG-response genes, SERPINs, and IL10 was also present in VF and RF. Bioinformatic deconvolution analysis showed that these signatures stemmed from general alterations in B cell and Monocyte/MDC gene activity. Conclusions: Tenofovir may impact the inflammasome in the rectal mucosa and set a balance between antiviral IFNs and proinflammatory cytokine signaling. This balance may be delicate in determining HIV infection risk outcomes. The above biomarkers may help monitor and identify mechanisms and targets of protection or infection risk in future microbiocide trials. Funding: MTN & NIH/NIAID/DAIDS IPCP Program (5U19AI082637). 881 Understanding Pain and Anxiety Experienced Around Long-Acting Injectable PrEP Kathrine Meyers 1 ; Kristina Rodriguez 1 ; Martin Markowitz 1 ; Sarit A. Golub 2 1 Aaron Diamond AIDS Rsr Cntr, New York, NY, USA; 2 Hunter Coll and the Grad Cntr, City Univ of New York, New York, NY, USA Background: Long-acting injectable PrEP may improve adherence and acceptability compared to daily oral dosing. However acceptability may be limited by anxiety about injections and concerns about injection site reactions (ISR), especially pain. We interviewed a subset of participants of a Phase 2 trial of cabotegravir long-acting injection (CAB LA). Methods: ÉCLAIR is a double-blind, randomized, multi-center study in 127 HIV-negative men at risk of HIV infection during which IM injections of 800mg CAB LA or PBO (saline) q12 weeks X 3 cycles were given. This substudy approached 48 participants who self-reported as MSM or male-to-female transgender women at 4 out of 10 sites and offered 30 randomly-selected individuals the opportunity to be interviewed. 2/28 who received placebo are excluded from results presented here. Interviewees included 27 MSM and one MTFT. Results: 23/28 (82.1%) reported ISR with a mean pain score of 2.8 out of 5. Of those 23 subjects, 13 (56.5%) reported that pain lasted more than three days. In a subset of men who were asked more details about the timing of pain, 37.5% (6/16) reported no pain during injections and 31.3% (5/16) reported no pain following injection. 75% (21/28) stated the first injection hurt less than expected. Anxiety before the first injection was felt by 20/28 (64.3%), however this decreased to just 8/28 (28.6%) by subsequent injections. There was no correlation between anxiety and pain. Despite discomfort and anxiety cited by a large proportion, interest in the product remained high: out of the subset of participants queried, 93.8% (15/16) reported that if proven effective, they would definitely or very likely use CAB-LA. In addition, 62.5% (10/16) reported that they would prefer to use CAB-LA every twelve weeks to daily oral PrEP.

Poster Abstracts

370

CROI 2016