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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>Intravaginal rings (IVRs) are attractive user-controlled delivery systems that can achieve sustained release of compounds for several weeks. We modeled in macaques a three-dimensional (3D)\u2013printed IVR delivering the investigational nucleoside reverse transcriptase translocator inhibitor islatravir (ISL). Three IVRs with 15, 30, or 60\u00a0milligrams of ISL were used in 30-day pharmacokinetic and safety studies followed by 90-day studies to identify a dose that maintains the concentration of the active intracellular metabolite islatravir triphosphate (ISL-TP) above protective benchmarks. IVRs were safe and delivered ISL in a dose-dependent manner. In a challenge study involving 12 weekly low-dose vaginal exposures to SHIV162p3, six macaques treated with 60-milligram ISL IVRs for 90 days remained seronegative and SHIV RNA negative, while two untreated controls were infected. These data provide initial preclinical evidence that a 90-day extended-release ISL IVR is safe and offers complete protection in a stringent challenge model, warranting further clinical investigation.<\/jats:p>","DOI":"10.1126\/sciadv.aef3514","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:59:39Z","timestamp":1787767179000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Dose-ranging pharmacokinetics, safety, and efficacy of a 90-day intravaginal ring delivering islatravir in pigtail macaques"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8426-6532","authenticated-orcid":true,"given":"Priya","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8986-6868","authenticated-orcid":true,"given":"Jasmine L.","family":"King","sequence":"additional","affiliation":[{"name":"Lampe Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9213-4178","authenticated-orcid":true,"given":"Jining","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella C.","family":"Young","sequence":"additional","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-8988","authenticated-orcid":true,"given":"Dawn","family":"Little","sequence":"additional","affiliation":[{"name":"Katmai Government Services (KGS), Anchorage, AK, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie L.","family":"Cottrell","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Sykes","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7026-7224","authenticated-orcid":true,"given":"Amanda P.","family":"Schauer","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9916-3325","authenticated-orcid":true,"given":"James","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-8493","authenticated-orcid":true,"given":"Angela D. 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