CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

88 ON-DEMAND HIV POSTEXPOSURE PROPHYLAXIS BY TAF/EVG VAGINAL INSERTS IN MACAQUES Charles Dobard 1 , M. Melissa Peet 2 , Kenji Nishiura 1 , Angela Holder 1 , Onkar N. Singh 2 , Timothy J. McCormick 2 , James Mitchell 1 , George Khalil 1 , Gerardo Garcia- Lerma 1 , Vivek Agrahari 2 , Pardeep Gupta 3 , Sriramakamal Jonnalagadda 3 , Walid Heneine 1 , Gustavo Doncel 2 , Meredith Clark 2 1 CDC, Atlanta, GA, USA, 2 CONRAD, Arlington, VA, USA, 3 University of the Sciences, Philadelphia, PA, USA Background: Topical products for HIV prevention that can be administered on-demand, either pre- or post-viral exposure, remain an advantageous regimen for end-users that have infrequent or clustered intercourse or are unable to take daily pills. CONRAD has developed a topical insert co-formulated with tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) to provide end-users a flexible on-demand dosing regimen that may align with their needs and lifestyle. Recently, we showed in a macaque model that mimics vaginal HIV transmission in women that a vaginal insert containing a fixed-dose combination of TAF and EVG was highly effective in preventing SHIV infection when administered 4 hours before virus exposure. Here, we investigated the efficacy of the same TAF/EVG insert when administered 4 hours after SHIV exposure. Methods: Normal cycling pigtail macaques (n=11) were exposed vaginally to SHIV162P3 once-weekly for 13 weeks. Six macaques received TAF/EVG inserts (20/16 mg) and 5 received a placebo. Inserts were placed in the posterior vagina near the cervix 4 hours after each SHIV exposure. Infection was monitored weekly by serology and RT-PCR of SHIV RNA in plasma. The concentrations of TAF, TFV, and EVG in plasma and TFV-DP in PBMCs were measured at 4 hours in a second group of 6 macaques that received the same TAF/EVG inserts once- weekly for 13 consecutive weeks. Results: Four of the 5 macaques that received placebo inserts became infected with SHIV after a median of 4 challenges (range 2-13). In contrast, all 6 macaques that received TAF/EVG inserts 4h after SHIV exposure remained protected after 13 challenges and a 20-week follow-up period (p=0.009; log-rank test). The calculated PEP efficacy of TAF/EVG inserts was 100%. Of the 78 plasma specimens collected 4h post insert dosing, EVG was only detected in 1 sample (15 ng/ml); none had detectable TFV or TAF. Conversely, TFV-DP was detected in 42/59 PBMC samples; median level in samples with detectable TFV-DP was 147.5 [range=15-993] fmol/10 6 cells. Conclusion: Vaginal administration of a single TAF/EVG insert several hours after virus exposure fully protected macaques against SHIV infection, thus increasing flexibility and expanding our established window of protection to 4 hours before or after sex. The observed high levels of TFV-DP in PBMCs by topical delivery of TAF is unique and may have contributed to protection. Our data support the clinical development of TAF/EVG inserts for on-demand PrEP/PEP for HIV prevention. 89LB WEEKLY ORAL ISLATRAVIR PROVIDES EFFECTIVE PEP AGAINST IV CHALLENGE WITH SIVMAC251 Martin Markowitz 1 , Agegnehu Gettie 2 , Leslie St. Bernard 1 , James Blanchard 2 , Brooke Grasperge 2 , Kerry Fillgrove 3 , Lingling Xue 3 , Neal Dube 3 , Daria Hazuda 3 , Jay Grobler 3 1 Aaron Diamond AIDS Research Center, New York, NY, USA, 2 Tulane National Primate Research Center, Covington, LA, USA, 3 Merck & Co, Inc, Kenilworth, NJ, USA Background: Islatravir (ISL, MK-8591, EFdA) is a novel nucleoside reverse transcriptase translocation inhibitor with robust antiviral activity and has demonstrated efficacy as weekly oral PrEP in the SHIV/Rhesus macaque (RM) rectal challenge model for doses ranging from 0.1 mg/kg to 3.9 mg/kg. We tested ISL’s efficacy as post-exposure prophylaxis (PEP) in the SIV/RM IV challenge model. Methods: 12 RM were challenged IV with 10 AID50 of SIVmac251. After 24 hr, 6 animals received 3.9 mg/kg ISL and 6 animals served as untreated controls. Treated animals in Stage I received a total of 4 weekly oral doses of ISL and were monitored for SIV infection for 7 wk after the 4th dose of ISL. In Stage II uninfected animals from Stage I were challenged as in Stage I and beginning 24h later 3 weekly oral doses of ISL at 3.9 mg/kg was initiated. Animals were monitored for 7 wk after the 3rd dose of ISL. Uninfected animals entered Stage III and were similarly challenged and treatment initiated at 24 h with 2 weekly oral doses of ISL at 3.9 mg/kg and animals monitored for 7 wk after the 2nd dose of ISL. Finally in Stage IV, uninfected animals were challenged IV and 24 hours later treated with a single oral dose of ISL at 3.9 mg/kg and followed for 7 wk. Animals were monitored for infection using RT-PCR and proviral

DNA amplification. Virus-specific antibody responses were measured using a commercial assay. Plasma ISL levels as well as ISL-triphosphate (ISL-TP) levels in PBMC were measured longitudinally. Results: All untreated control animals were viremic 7 days after IV challenge with SIVmac251. 6/6 treated animals were completely protected in Stages I-III (Fisher’s exact test P=0.0022). ISL-TP levels became undetectable in PBMC 3 weeks on average after the last ISL oral dose. In Stage IV, two of 6 animals became infected with wild type SIVmac251, one with viremia at day 14 ([ISL-TP] < 0.02 pmol/10 6 PBMCs ) and another at day 49 (Fisher’s exact test P=0.06). Conclusion: As few as 2 weekly oral doses of ISL at 3.9 mg/kg given 24h after IV challenge with SIVmac251 completely prevented infection. However, a single ISL dose 24h after IV challenge failed to provide statistically significant protection. As the ISL-TP T 1/2 in human PBMCs (79-214 hr) is substantially longer than RM (50 hr), it is conceivable that a single low oral dose given within 24 hours of HIV exposure may provide effective PEP. These results support the potential utility of ISL as a simplified PEP agent. 90 PHASE I PLACEBO-CONTROLED SAFETY, PK, AND PD STUDY OF MB66 ANTI-HIV AND ANTI-HSV FILM Susan Cu-Uvin 1 , Thomas Moench 2 , Joseph A. Politch 3 , Karen T. Tashima 1 , Jai G. Marathe 3 , Kate M. Guthrie 1 , Howard Cabral 3 , Tara J. Nyhuis 2 , Miles Brenna 2 , Larry Zeitlin 2 , Hans M. Spiegel 4 , Kenneth H. Mayer 5 , Kevin Whaley 2 , Deborah Anderson 3 1 Brown University, Providence, RI, USA, 2 Mapp Biopharmaceutical, Inc, San Diego, CA, USA, 3 Boston University, Boston, MA, USA, 4 NIH, Rockville, MD, USA, 5 Harvard University, Cambridge, MA, USA Background: Monoclonal antibodies(mAbs)show promise as multipurpose prevention technology.The MB66 intravaginal film contains 10 mg each of anti-HIV(VRC01) and anti-HSV(HSV8) mAbs to provide protection against two incurable viral infections. Methods: The active film or vehicle control filmwas randomly assigned at a 1:1 ratio to 29 healthy sexually abstinent women who were instructed to insert 1 film daily for 7 days.Visits and clinical sampling occurred predose at 1, 4, 24 hrs after the 1st dose and 24 hrs, 6-10 days after the 7th dose. Cervicovaginal lavage samples (CVLs) were assayed by Luminex for 16 cytokines that have been associated with HIV transmission,by TZM-bl assay for HIV neutralization[strains:Q23-1 (R5 clade A), BaL (R5 clade B),and LAI (X4 clade B)],and by Plaque Reduction NeutralizationTest for HSV-2 neutralization [HSV-2 strain G].CVLs and TearFlo samples(4 vaginal sites)were assessed by ELISA for VRC01 and HSV8 mAb concentrations. Results: There were 45 AEs;19 were deemed related to study product, but were balanced between active and placebo film (p’s=1.0).There were no serious AEs(SAEs) and no significant differences in levels of proinflammatory cytokines, Nugent Scores,vaginal pH between Active and Placebo film groups(p’s>0.10). Acceptability and willingness to use the product were judged to be high by post-use ACASI questionnaire.Concentrations of VRC01 and HSV8 increased significantly in vaginal secretions following insertion of Active film.Antibody levels in TearFlo samples peaked at 1 hr post-dosing (median:35 µg/mL) but remained significantly elevated at 24 hours post 1st and 7th film. (median: ~ 1.8 µg/mL). In light of an estimated dilution factor of 35 for the TearFlo samples,the extrapolated VRC01 concentrations range from 63-1,225 times IC 50 for VRC01(~1 µg/mL).CVLs from the active film group, collected 24 hr after 1st film and 7th films,significantly neutralized all 3 HIV strains and HSV-2. Conclusion: Repeated doses of MB66 filmwas safe and tolerated.Significant HIV-1 and HSV-2 neutralization (ex vivo) was observed at 24 hrs,7 films. Antibody levels in vagina had concentrations consistent with protection for up to 24 hrs.

Oral Abstracts

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CROI 2020