{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:12:17Z","timestamp":1791389537140,"version":"4.3.3"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences, Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resistance analyses conducted in a Phase 1b study of lenacapavir (Study 4072) in people with HIV (PWH).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Mutations were inserted in a proviral DNA clone by site-directed mutagenesis, and viruses (n = 12) were generated by transfection. Sequences were used to generate single-cycle (SC) test vectors that were evaluated in a Gag-Pro assay, and replicative viruses were tested in a multicycle (MC) MT-2 assay to determine lenacapavir susceptibility. Study 4072 was a Phase 1b, double-blinded, placebo-controlled, dose-ranging, randomized study of lenacapavir in untreated PWH. Participants received a single dose of lenacapavir (up to 750 mg) or placebo (10 day monotherapy). CA resistance was characterized using genotypic and\/or phenotypic assays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Lenacapavir susceptibility in the SC assay showed an inverse relationship between replication capacity and resistance. In Study 4072, all 29 participants receiving lenacapavir showed a robust virological response with no rebound. At baseline, no participant had resistance mutations to lenacapavir, and all had WT susceptibility to lenacapavir. Post-monotherapy analyses revealed the emergence of CA mutation Q67H at Day 10 in two participants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In vitro assays confirmed that increased resistance to lenacapavir was associated with decreased replication capacity of mutant viruses. In the clinical study no pre-existing lenacapavir resistance was detected. Emergence of Q67H occurred at exposures below the dose used in current Phase 2\/3 studies. These results support development of lenacapavir as an antiretroviral agent.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkab503","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T20:09:09Z","timestamp":1641326949000},"page":"989-995","source":"Crossref","is-referenced-by-count":59,"title":["Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study"],"prefix":"10.1093","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0911-4237","authenticated-orcid":false,"given":"Nicolas","family":"Margot","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Vanderveen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidula","family":"Naik","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Ram","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"PC","family":"Parvangada","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Martin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Rhee","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Callebaut","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"2022033111263970200_dkab503-B1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/s41586-020-2443-1","article-title":"Clinical targeting of HIV capsid protein with a long-acting small molecule","volume":"584","author":"Link","year":"2020","journal-title":"Nature"},{"key":"2022033111263970200_dkab503-B2","article-title":"GS-6207, A Potent and Selective First-in-Class Long-Acting HIV-1 Capsid Inhibitor","author":"Yant"},{"key":"2022033111263970200_dkab503-B3","article-title":"ACTIVITY AND RESISTANCE CHARACTERIZATION OF THE HIV CAPSID INHIBITOR LENACAPAVIR","author":"VanderVeen"},{"key":"2022033111263970200_dkab503-B4","doi-asserted-by":"crossref","first-page":"e02057-20","DOI":"10.1128\/AAC.02057-20","article-title":"Absence of lenacapavir (GS-6207) phenotypic resistance in HIV gag cleavage site mutants and in isolates with resistance to existing drug classes","volume":"65","author":"Margot","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2022033111263970200_dkab503-B5","article-title":"In Vitro Resistance Profile of GS-6207, a First-in-Class Picomolar HIV Capsid Inhibitor in Clinical Development as a Novel Long-Acting Antiretroviral Agent","author":"Yant"},{"key":"2022033111263970200_dkab503-B6","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1093\/jac\/dkaa060","article-title":"Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients","volume":"75","author":"Marcelin","year":"2020","journal-title":"J Antimicrob 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