| Autor: |
Fernanda P. Pons-Faudoa, Nicola Di Trani, Simone Capuani, Jocelyn Nikita Campa-Carranza, Bharti Nehete, Suman Sharma, Kathryn A. Shelton, Lane R. Bushman, Farah Abdelmawla, Martin Williams, Laura Roon, David Nerguizian, Corrine Ying Xuan Chua, Michael M. Ittmann, Joan E. Nichols, Jason T. Kimata, Peter L. Anderson, Pramod N. Nehete, Roberto C. Arduino, Alessandro Grattoni |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.15.520646 |
| Popis: |
The impact of pre-exposure prophylaxis (PrEP) on slowing the global human immunodeficiency virus (HIV) epidemic hinges on effective drugs and delivery platforms. Oral regimens have represented the pillar of HIV PrEP for years. However, variable adherence has spurred development of long-acting delivery systems, which also aim at increasing PrEP access, uptake and persistence. Here we present an ultra-long-acting and transcutaneously refillable subcutaneous nanofluidic implant for constant and sustained release of islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, for HIV PrEP. In rhesus macaques, the ISL-eluting implants (nISL) achieved constant plasma ISL levels (median 3.14 nM) and peripheral blood mononuclear cells (PBMCs) ISL-triphosphate levels (ISL-TP) (median 0.16 pmol/106cells) for over 20 months uninterrupted. These drug concentrations are above the established PrEP protection threshold. In two non-blinded, placebo-controlled studies with repeated low-dose rectal and vaginal SHIVSF162P3challenges in male and female rhesus macaques, respectively, nISL implants conferred 100% protection against infection (p=0.0005 and 0.0009, respectively between nISL and placebo control groups). The nISL implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month period. Overall, our refillable nISL implant is a promising ultra-long-acting delivery technology for HIV PrEP.One Sentence SummaryAn ultra-long-acting and subcutaneous refillable nanofluidic implant achieved preventive levels of islatravir in non-human primates for 20 months without refilling and conferred 100% protection against rectal and vaginal SHIV transmission. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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