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In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian\/human immunodeficiency virus (SHIV) infection of macaques. Single TFV HOsm high-dose douches achieved peak plasma TFV levels similar to daily oral PrEP, while other formulations yielded lower concentrations. Rectal tissue TFV-diphosphate (TFV-DP) concentrations at the portal of virus entry, however, were markedly higher after HOsm douching than daily oral PrEP. Repeated douches led to significantly higher plasma TFV and higher TFV-DP concentrations in rectal tissue at 24 hours compared with single douches, without detectable mucosal or systemic toxicity. Using stringent repeated intrarectal SHIV exposures, single HOsm high-dose douches delivered greater protection from virus acquisition for more than 24 hours compared with oral PrEP. Our results demonstrate a rapid delivery of protective TFV doses to the rectal portal of virus entry as a potential low-cost and safe PrEP alternative.<\/jats:p>","DOI":"10.1172\/jci.insight.161577","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T14:01:03Z","timestamp":1670421663000},"source":"Crossref","is-referenced-by-count":3,"title":["Hypo-osmolar rectal douche tenofovir formulation prevents simian\/human immunodeficiency virus acquisition in macaques"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-8400","authenticated-orcid":true,"given":"Peng","family":"Xiao","sequence":"first","affiliation":[{"name":"New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9048-2717","authenticated-orcid":true,"given":"Sanjeev","family":"Gumber","sequence":"additional","affiliation":[{"name":"Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1670-8786","authenticated-orcid":true,"given":"Mark A.","family":"Marzinke","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine;"},{"name":"Department of Pathology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy","family":"Hoang","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine; and"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3592-2841","authenticated-orcid":true,"given":"Rohan","family":"Myers","sequence":"additional","affiliation":[{"name":"New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-882X","authenticated-orcid":true,"given":"Abhijit A.","family":"Date","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine; and"},{"name":"Department of Pharmacology and Toxicology, R. 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