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Prior trials of a 25\u00a0mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV\u20101 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three\u2010month rings with different DPV dosages, compared with the monthly DPV ring.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>From December 2017 to October 2018, MTN\u2010036\/IPM\u2010047 enrolled 49 HIV\u2010negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three\u2010month) rings (100 or 200\u00a0mg DPV) to a monthly 25\u00a0mg DPV ring, each used over 13\u00a0weeks, with follow\u2010up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were no differences in the proportion of participants with grade \u22652 genitourinary AEs or grade \u22653 AEs in the extended duration versus monthly ring arms (<jats:italic>p<\/jats:italic>\u00a0=\u00a01.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200\u00a0mg ring respectively. Cervical tissue concentrations were consistently higher in the 200\u00a0mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations\/outages) with no differences between the monthly versus three\u2010month rings. Most participants found the ring acceptable (median = 8 on 10\u2010point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25\u00a0mg arm (73%) compared with the 100\u00a0mg (25%) and 200\u00a0mg (44%) arms (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.01 and <jats:italic>p<\/jats:italic>\u00a0=\u00a00.15 respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The extended duration DPV rings were well\u2010tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three\u2010month DPV rings for HIV prevention.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.25747","type":"journal-article","created":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T13:10:55Z","timestamp":1623503455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0320-823X","authenticated-orcid":false,"given":"Albert Y","family":"Liu","sequence":"first","affiliation":[{"name":"Bridge HIV San Francisco Department of Public Health San Francisco CA USA"},{"name":"Department of Medicine University of California San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dominguez Islas","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research Center Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Gundacker","sequence":"additional","affiliation":[{"name":"Statistical Center for HIV\/AIDS Research &amp; Prevention Fred Hutchinson Cancer Research Center Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blazej","family":"Neradilek","sequence":"additional","affiliation":[{"name":"Statistical Center for HIV\/AIDS Research &amp; Prevention Fred Hutchinson Cancer Research Center Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Hoesley","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8536-648X","authenticated-orcid":false,"given":"Ariane","family":"van der Straten","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Francisco CA USA"},{"name":"Women\u2019s Global Health Imperative (WGHI) RTI International Berkeley CA USA"},{"name":"ASTRA Consulting Kensington CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5696-8665","authenticated-orcid":false,"given":"Craig W","family":"Hendrix","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-100X","authenticated-orcid":false,"given":"May","family":"Beamer","sequence":"additional","affiliation":[{"name":"Magee\u2010Womens Research Institute Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy E","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Magee\u2010Womens Research Institute Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"McClure","sequence":"additional","affiliation":[{"name":"FHI 360 Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Harrell","sequence":"additional","affiliation":[{"name":"Statistical Center for HIV\/AIDS Research &amp; 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