{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T22:28:50Z","timestamp":1749421730983,"version":"3.41.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100005369","name":"Danish Ministry of Foreign Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005369","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Flanders Ministry of Foreign Affairs"},{"DOI":"10.13039\/100009099","name":"Irish Aid","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009099","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007729","name":"Ministry of Foreign Affairs of the Netherlands","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007843","name":"Norwegian Agency for Development Cooperation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020171","name":"UK Government's Foreign, Commonwealth & Development Office","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000200","name":"US Agency for International Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000200","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill & Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007921","name":"University of Pittsburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007921","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The Ring Study demonstrated 35.1% human immunodeficiency virus type 1 (HIV-1) infection risk reduction among participants who used the Dapivirine vaginal ring-004 (DVR), whereas the Dapivirine Ring Extended Access and Monitoring (DREAM) trial, approximated a 62% risk reduction. The observed non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs) and effects on viral susceptibility are described here.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Population-based genotyping on plasma samples collected longitudinally, and next-generation sequencing (NGS) and phenotypic susceptibility testing were done on plasma collected at seroconversion. Retrospective HIV-1 RNA testing was used to more accurately establish the time of infection.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In the Ring Study, NNRTI RAMs were not observed in most viruses at seroconversion (population-based genotyping: DVR: 71 of 84, 84.5%; placebo: 50 of 58, 86.2%). However, more E138A was found in the DVR group (E138A DVR: 9 of 84, 10.7%; placebo: 2 of 58, 3.4%; P = .2, Fisher exact test). NGS detected 1 additional mutation in each group (DVR: G190A; placebo: G190A and G190E). Marginal dapivirine susceptibility reduction was found with NNRTI RAMs at seroconversion (geometric mean fold-change, range: DVR, 3.1, 1.3\u20135.1; placebo, 5.8, 0.9\u2013120). NNRTI RAMs were not emergent between first detectable HIV-1 RNA and seroconversion when these visits differed (paired samples, mean ring use: DVR, n = 52, 35 days; placebo, n = 26, 31 days). After stopping DVR, 2 of 63 viruses had emergent G190G\/A or K103K\/N with V106V\/M at final study visit. Resistance profiles from the DREAM trial were consistent with the Ring Study.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>DVR showed little potential for selection of NNRTI-resistant variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Trials Registration<\/jats:title>\n                  <jats:p>NCT01539226 and NCT02862171.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciac875","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T16:58:08Z","timestamp":1667581088000},"page":"996-1002","source":"Crossref","is-referenced-by-count":4,"title":["Characterization of Viruses in Phase 3 and Phase 3b Trials (the Ring Study and the Dapivirine Ring Extended Access and Monitoring Trial) of the Dapivirine Vaginal Ring for Human Immunodeficiency Virus Type 1 Infection Risk Reduction"],"prefix":"10.1093","volume":"76","author":[{"given":"John","family":"Steytler","sequence":"first","affiliation":[{"name":"International Partnership for Microbicides South Africa NPC , Johannesburg ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Craig","sequence":"additional","affiliation":[{"name":"Research Virology Consulting Ltd , Cambridgeshire ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elna","family":"van der Ryst","sequence":"additional","affiliation":[{"name":"Independent Consultant , Kent ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Van Baelen","sequence":"additional","affiliation":[{"name":"BVB Clin Consult BVBA , Herent ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Nuttall","sequence":"additional","affiliation":[{"name":"International Partnership for Microbicides , Silver Spring, Maryland ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neli\u00ebtte","family":"van Niekerk","sequence":"additional","affiliation":[{"name":"International Partnership for Microbicides South Africa NPC , Johannesburg ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Mellors","sequence":"additional","affiliation":[{"name":"Microbicide Trials Network Virology Core Laboratory, University of Pittsburgh , Pittsburgh, Pennsylvania ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urvi","family":"Parikh","sequence":"additional","affiliation":[{"name":"Microbicide Trials Network Virology Core Laboratory, University of Pittsburgh , Pittsburgh, Pennsylvania ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole","family":"Wallis","sequence":"additional","affiliation":[{"name":"Bio-Analytical Research Corporation Laboratory and Lancet Laboratories , Johannesburg ,","place":["South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Ring Study and the DREAM Trial Study Teams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,11,8]]},"reference":[{"author":"European Medicines Agency","key":"2025052320022604800_ciac875-B1"},{"key":"2025052320022604800_ciac875-B2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.pbiomolbio.2004.07.001","article-title":"Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase 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development for the prevention of HIV-1 infection","volume":"61","author":"Giacobbi","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025052320022604800_ciac875-B6","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1128\/AAC.05821-11","article-title":"In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine","volume":"56","author":"Schader","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2025052320022604800_ciac875-B7","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1128\/AAC.01426-10","article-title":"Human immunodeficiency virus type 1 resistance or cross-resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides","volume":"55","author":"Selhorst","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2025052320022604800_ciac875-B8","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1016\/S2352-3018(20)30300-3","article-title":"Safety, 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