TY - JOUR
T1 - Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates
AU - Pons-Faudoa, Fernanda P.
AU - Trani, Nicola Di
AU - Capuani, Simone
AU - Campa-Carranza, Jocelyn Nikita
AU - Nehete, Bharti
AU - Sharma, Suman
AU - Shelton, Kathryn A.
AU - Bushman, Lane R.
AU - Abdelmawla, Farah
AU - Williams, Martin
AU - Roon, Laura
AU - Nerguizian, David
AU - Chua, Corrine Ying Xuan
AU - Ittmann, Michael M.
AU - Nichols, Joan E.
AU - Kimata, Jason T.
AU - Anderson, Peter L.
AU - Nehete, Pramod N.
AU - Arduino, Roberto C.
AU - Grattoni, Alessandro
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved;
PY - 2023/6/28
Y1 - 2023/6/28
N2 - The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP. In rhesus macaques, the islatravir-eluting implants achieved constant concentrations of islatravir in plasma (median 3.14 nM) and islatravir triphosphate in peripheral blood mononuclear cells (median 0.16 picomole per 106 cells) for more than 20 months. These drug concentrations were above the established PrEP protection threshold. In two unblinded, placebo-controlled studies, islatravir-eluting implants conferred 100% protection against infection with SHIVSF162P3 after repeated low-dose rectal or vaginal challenge in male or female rhesus macaques, respectively, compared to placebo control groups. The islatravir-eluting implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month study period. This refillable islatravir-eluting implant has potential as a long-acting drug delivery system for HIV PrEP.
AB - The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP. In rhesus macaques, the islatravir-eluting implants achieved constant concentrations of islatravir in plasma (median 3.14 nM) and islatravir triphosphate in peripheral blood mononuclear cells (median 0.16 picomole per 106 cells) for more than 20 months. These drug concentrations were above the established PrEP protection threshold. In two unblinded, placebo-controlled studies, islatravir-eluting implants conferred 100% protection against infection with SHIVSF162P3 after repeated low-dose rectal or vaginal challenge in male or female rhesus macaques, respectively, compared to placebo control groups. The islatravir-eluting implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month study period. This refillable islatravir-eluting implant has potential as a long-acting drug delivery system for HIV PrEP.
KW - Animals
KW - Male
KW - Female
KW - Anti-HIV Agents/pharmacology
KW - Macaca mulatta
KW - HIV Infections/prevention & control
KW - Leukocytes, Mononuclear
KW - Drug Delivery Systems
UR - http://www.scopus.com/inward/record.url?scp=85163696998&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163696998&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adg2887
DO - 10.1126/scitranslmed.adg2887
M3 - Article
C2 - 37379369
AN - SCOPUS:85163696998
SN - 1946-6234
VL - 15
SP - eadg2887
JO - Science translational medicine
JF - Science translational medicine
IS - 702
M1 - eadg2887
ER -