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PrEP New in Development & Current at HIVR4P
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Cabotegravir (CAB) Long-Acting (LA) Phase 3 (Ph3) PrEP Dose Selection Based on Population Pharmacokinetics (PPK) in Healthy and HIV-Infected Adults - (10/30/18)
Acceptability of long-acting injectable cabotegravir (CAB LA) in HIV-uninfected individuals: HPTN 077 - (10/25/18)
Pharmacokinetic and Pharmacodynamic Evaluation of the Antiretroviral Compound MK-2048 Released From an Intravaginal Ring in Rhesus Macaques - (10/30/18)
Beyond TDF/FTC: The Future of Systemic Pre-exposure Prophylaxis - (10/29/18)
"AMP" PREP Broadly Neutralizing Antibody Studies / Next Generation PrEP / Tracking Global PrEP Use - (10/29/18)
Long-term Delivery of Anti-HIV Monoclonal Antibodies with Gene Therapy Approach in Monkeys - (10/26/18)
Global Update: State of Oral PrEP Implementation and Scale-up - (10/30/18)
HIV Incidence in Persons Using Truvada (FTC/TDF) for HIV Pre-exposure Prophylaxis (PrEP): Worldwide Experience From 46 Studies - (10/26/18)
NATAP REPORTS Coverage:
HIV Research for Prevention (HIVR4P)
October 21-25, 2018
Madrid
Dapivirine Vaginal Ring Next Steps: Study Results Review, Planning for Introduction & Access, Regulatory Overview - (10/24/18)
Safety and Pharmacokinetics of Dapivirine and Levonorgestrel Vaginal Rings for Multipurpose Prevention of HIV and Pregnancy
Sharon L. Achilles1, Craig W. Hendrix3, Samuel M. Poloyac4, Craig J. Hoesley5, Melissa Peda6, Holly Gundacker6, Barbara S. Mensch7, Mark A. Marzinke3, Brid Devlin8, Annalene M. Nel8, Jeanna M. Piper9, Sherri Johnson10, Beatrice A. Chen1 1University of Pittsburgh, United States, 2Magee-Womens Research Institute, United States, 3Johns Hopkins University School of Medicine, United States, 4University of Pittsburgh School of Pharmacy, United States, 5University of Alabama at Birmingham, United States, 6Statistical Center for HIV/AIDS Research & Prevention/Fred Hutchinson Cancer Research Center, United States, 7Population Council, United States, 8International Partnership for Microbicides, United States, 9NIAID, National Institutes of Health, United States, 10FHI 360, United States
Background: Vaginal rings can offer sustained multi-drug delivery for HIV pre-exposure prophylaxis and contraception as multipurpose prevention technology (MPT). A 90-day MPT vaginal ring containing dapivirine (DPV) and levonorgestrel (LNG) has been developed. Given the greater drug quantities in these rings compared with other DPV or LNG single-drug rings, this study was designed to assess initial safety and drug pharmacokinetics. We compared MPT rings to DPV-only rings.
Methods: In this Phase 1, multi-site, double-blind, randomized (1:1), two-arm trial, 24 HIV-negative, healthy, sexually abstinent women were randomized to use vaginal rings containing 200 mg DPV with or without 320 mg LNG for 14 days. We assessed safety by adverse events (AE) and adherence by self-report. We quantified DPV and LNG in plasma and vaginal fluid by mass spectrometry.
Results: Median age was 31.0 years (range 20-43); 14 (61%) were white, 7 (30%) were black, and 2 (9%) were mixed race for 23 evaluable participants. Retention was 99%. There were 43 total reported AEs, 36 Grade 1 and 7 Grade 2. The number of women with related Grade 2 genitourinary AEs in the DPV vs DPV/LNG arms did not differ (2/11 (18%) vs 0/12 (0%), p=.2). No Grade 3 or higher AEs were reported. All participants reported full adherence to within 15-min over 14-days. Median plasma DPV Cmax trended higher in DPV/LNG compared to DPV users (661 vs 499 pg/mL, respectively, p=.05). Median vaginal fluid DPV Cmax was not significantly different between DPV/LNG and DPV users (183 vs 107 ng/mL, respectively, p=.09). The median plasma DPV t1/2 was 50h (IQR 37-52h) for the MPT ring. Two days after MPT ring removal, plasma DPV remained 369 pg/mL. Median plasma LNG Cmax was 1.6 ng/mL (IQR 1.1-2.6).
Conclusions: The achieved local and systemic DPV and LNG concentrations supports further evaluation of this MPT vaginal ring. Both formulations were well-tolerated and no safety concerns were identified. Based on these promising results a 90-day evaluation of the MPT ring is underway.
WEBCAST: http://webcasts.hivr4p.org/console/player/40402?mediaType=slideVideo&&crd_fl=1&ssmsrq=1540932677606&ctms=5000&csmsrq=3312
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Dose-ranging Pharmacokinetic Assessment of Vaginally Administered EVG/TAF Inserts in Macaques for PrEP
Charles Dobard1, Melissa Peet2, Kenji Nishiura1, Onkar Singh2, Pardeep Gupta3, Chuong Dinh1, Angela Holder1, Gerardo Garcia-Lerma1, Wei Zhang2, Sriramakamal Jonnalagadda3, Denise Caplena2, Jill Schwartz2, Walid Heneine1, Gustavo Doncel2, Meredith Clark2 1Centers for Disease Control and Prevention, United States, 2CONRAD Eastern Virginia Medical School, United States, 3University of the Sciences, United States
Background: On-demand topical PrEP for HIV prevention has several benefits over a daily oral PrEP regimen including reduced costs, limited drug toxicity, and potentially increased adherence. To maximize adherence and effectiveness, a wide window of protection is needed to support a flexible on-demand dosing regimen. CONRAD is developing an elvitegravir/tenofovir alafenamide (EVG/TAF) combination insert intended for vaginal or rectal on-demand use. When administered topically, EVG provides the advantage of immediate bioavailability and rapid accumulation in mucosal tissues, while TAF is rapidly converted to the active metabolite TFV-DP that has a long intracellular half-life and proven PrEP efficacy. Here, we conducted a dose-ranging PK of vaginally administered EVG/TAF inserts in macaques.
Methods: Inserts containing EVG/TAF were prepared at three dose levels: 8/10, 16/20 and 24/40 mg. Pigtail macaques (n=4/dose) were administered inserts intravaginally and plasma, vaginal fluid (VF), and vaginal biopsies (Vbx) were collected at 2, 4, and 24h. EVG and TFV was measured in all 3 matrices and TFV-DP in tissues.
Results: The PK profiles from all 3 inserts were similar and demonstrated minimal dose dependence. Bioanalysis showed EVG and TFV were detected at high levels in VF (med Cmax = 276 and 158 ug/ml, respectively) 2-4h post dosing. Likewise, EVG levels in Vbx at 4h were high (med Cmax = 1.9 x 105 ng/g) and exceeded EVG PA-IC95 (45 ng/mL). Median TFV-DP levels in Vbx were also high at 4h (767 fmol/mg) and increased at 24h (1,197 fmol/mg) to levels in range with those shown to provide in vivo protection in macaques. Median EVG and TFV levels in plasma were below the limit of quantitation.
Conclusions: Adequate EVG and TFV-DP mucosal concentrations support further investigation of EVG/TAF inserts for on-demand topical PrEP. In vivo efficacy of EVG/TAF inserts in a vaginal SHIV macaque model is currently underway. Human clinical studies are also planned for EVG/TAF inserts administered vaginally or rectally.
WEBCAST: http://webcasts.hivr4p.org/console/player/40421?mediaType=slideVideo&&crd_fl=1&ssmsrq=1540929776030&ctms=5000&csmsrq=1449
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Tenofovir Douche for PrEP: On-demand, Behaviorally-congruent Douche Rapidly Achieves Colon Tissue Concentration Targets (DREAM 01 Study)
Ethel Weld1, Edward Fuchs1, Mark Marzinke1,1, Peter Anton2, Ken Ho3, Rahul Bakshi1, Jarrett Engstrom4, Julie Elliott2, Lisa Rohan4, Cindy Jacobson4, Hans Spiegel5, Alex Carballo-Dieguez6,7, Rebecca Giguere6,7, Ian McGowan3, Craig Hendrix1 1Johns Hopkins University School of Medicine, United States, 2UCLA AIDS Institute, United States, 3University of Pittsburgh School of Medicine, United States, 4Magee-Womens Research Institute, United States, 5NIAID, NIH, United States, 6Columbia University, United States, 7New York State Psychiatric Institute, United States
Background: Condomless receptive anal sex carries a high risk of HIV transmission. Efficacy of oral tenofovir (TFV)-based pre-exposure prophylaxis (PrEP) depends on consistent adherence and some systemic toxicity. Both may be avoided by a single dose TFV douche before sex as an on demand, behaviorally-congruent PrEP strategy for those struggling with daily oral PrEP or preferring topical methods.
Methods: Healthy, HIV-uninfected men who have sex with men (MSM) received a single dose of 3, 125mL TFV douches a month apart. Six participants received each douche - Product A 220mg TFV in saline, Product B 660mg TFV in saline, Product C 660mg TFV in half-normal saline. We collected blood and colorectal samples for one week to assess TFV, it's active form, TFV-diphosphate (TFV-DP), and histology.
Results: All 3 douches showed excellent safety with no Grade 2 or higher product-related adverse events, and no histologic changes. Median peak plasma TFV was 8, 11 and 19 ng/mL for Products A, B, and C, respectively, well below daily oral TFV disoproxil fumarate [TDF] plasma trough concentrations. Median colorectal tissue cell TFV-DP concentrations exceeded our target concentration within 1 to 3 hours (first time point assessed) and, over the first 24 hours, exceeded target by 1.3 log10, 2.4 log10, and 5.0 log10 with Products A, B, and C, respectively. Our target, 83 fmol/106 cells, was based on 4 TDF dose/week, proven highly protective in iPrEx.
Conclusions: Single dose TFV douches were safe, well tolerated, and far exceeded target concentrations for 24 hours after dosing. In macaques, the same Product C showed a high degree of protection from weekly rectal SHIV challenges (83% protected) compared to oral daily TDF (50% protected). In addition, in an online survey of 4,751 MSM, 80% reported douching before RAI and >95% indicated willingness to use a douche as PrEP regardless of current douching practices. These findings encourage continued clinical development of an on demand, behaviorally-congruent TFV douche for PrEP.
WEBCAST: http://webcasts.hivr4p.org/console/player/40469?mediaType=slideVideo&&crd_fl=1&ssmsrq=1540932025351&ctms=5000&csmsrq=1224
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Development of an End-user Informed Tenofovir Alafenamide (TAF) Implant for Long-acting (LA)-HIV Pre-exposure Prophylaxis (PrEP)
Gregory J. Gatto1, Rhonda M. Brand2, Natalie Girouard1, Linying A. Li1, Leah Johnson1, Mark A. Marzinke3, Emily Krogstad4, Aaron Siegel5, Emily Helms5, Zach Demkovich4, Ellen Luecke4, Ariane van der Straten4 1RTI International, United States, 2University of Pittsburgh, United States, 3Johns Hopkins University, United States, 4Women's Global Health Imperative, RTI International, United States, 5Magee-Womens Research Institute, United States
Background: Implants promise systemic LA-HIV PrEP delivery while minimizing user burden. Our polycaprolactone (PCL) implant device was re-engineered to a more scalable design that is better aligned with the preferred attributes of a subdermal implant for HIV PrEP as expressed by both medical providers and end users. Here, we assessed the pharmacokinetics and safety of sustained TAF delivery through improved flexible rod-shaped reservoir implants.
Methods: Extruded PCL tubes (40 mm x 2.5 mm) were loaded with a slurry of TAF and castor oil. Ten female rabbits received two implants (one active and one placebo, or two active) subcutaneously inserted via trocar in the dorsal space. Identical TAF implants were concurrently evaluated in vitro. During the 63-d study, rabbits were sampled for plasma TAF/TFV and peripheral blood mononuclear cells (PBMCs) tenofovir-diphosphate (TFV-DP) weekly, and cervical and vaginal tissue TFV-DP on d63.
Results: In vitro TAF release from the implants demonstrated zero-order release kinetics with implants performing as designed, delivering 0.14±0.01 mg/d (low dose) and up to 0.72±0.01 mg/d (high dose). In vivo, PBMC TFV-DP levels of 443±529 fmol/106 and 1293±905 fmol/106 were sustained by the low dose and high doses, respectively. On d63, median vaginal and cervical tissue TFV-DP levels of 139 fmol/mg and 74 fmol/mg were achieved in the high dose group. The plasma TAF/TFV levels were maintained for the study duration. Minimal tissue reactivity at the insertion sites was noted. Residual drug analysis of the retrieved implants indicated similar in vivo and in vitro TAF release rates.
Conclusions: TAF device implants were effectively inserted with an approved trocar, well tolerated, and easily retrieved intact from rabbits after >60 days. All implants delivered TAF and maintained PBMC TFV-DP at putative protective concentrations for the study duration, suggesting our re-designed TAF implant device is suitable for continued development as a long-acting subdermal implant for HIV PrEP.
WEBCAST: http://webcasts.hivr4p.org/console/player/40468?mediaType=slideVideo&&crd_fl=1&ssmsrq=1541329944051&ctms=5000&csmsrq=1338
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A Subcutaneous Biodegradable Implant for Sustained Delivery of Tenofovir Alafenamide (TAF) for HIV Pre-exposure Prophylaxis (PrEP)
Natalie Girouard1, Leah Johnson1, Ellen Luecke1, Zach Demkovich1, Teresa Jester1, Alice Li1, Pafio Johnson1, Ariane van der Straten1 1RTI International, United States
Background: Although oral PrEP is efficacious, daily dosing is burdensome. Long-acting delivery methods reduce burden by being provider-administered, discrete and protective over several months. We are developing a subcutaneous biodegradable implant for sustained delivery of TAF >6 months for HIV PrEP.
Methods: Polycaprolactone (PCL, molecular weight (Mn) = 45 and 80 kDa) tubes (2.5 x 40 mm) were extruded, filled with a TAF and excipient formulation, and enclosed by heat sealing. The implants were incubated in 1X PBS at 37°C and transferred to fresh buffer three times per week to maintain sink conditions. TAF concentrations were calculated from UV absorbance at 260 nm; stability was assessed via chromatography.
Results: Extrusion offered a scalable method for producing reservoir-style implants with controlled wall thickness (45, 70, 100, and 200 μm) for tuning TAF delivery via zero-order Fickian diffusion kinetics. Various parameters controlled TAF release rates: wall thickness, excipient, and PCL Mn, where thinner tubes, castor oil formulations, and 80 kDa PCL resulted in faster release kinetics. Castor oil formulated implants with wall thicknesses ≥100 μm demonstrated sustained release >120 days. Implants retained TAF purity ≥95% when exposed to 40°C/75% relative humidity in a sealed foil package >180 days. The diffusion-partition coefficients for TAF and PCL were 1.6x10-11 and 4.6x10-13 m2/s for sesame and castor oil formulations, respectively. Control of formulation and thickness resulted in TAF daily release rates from 0.21 mg/day (sesame oil 70 μm 45 kDa PCL) to 1.3 mg/day (castor oil 45 μm 80 kDa PCL). The ability to adjust PCL Mn affords tunability to implant biodegradation time frame.
Conclusions: We demonstrated tunable release rates of TAF over an order of magnitude for >4 months from an implant that has excellent shelf stability and is amenable to scalable manufacturing. We are currently adjusting TAF payload, formulation, and wall thickness to demonstrate optimized implants with >6 months release.
WEBCAST:
http://webcasts.hivr4p.org/console/player/40468?mediaType=slideVideo&&crd_fl=1&ssmsrq=1540932389046&ctms=5000&csmsrq=2597
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