{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T10:28:03Z","timestamp":1758709683950},"reference-count":35,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2009,3,1]],"date-time":"2009-03-01T00:00:00Z","timestamp":1235865600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2009,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-nai\u0308ve human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and<jats:italic>env<\/jats:italic>sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual\/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for<jats:italic>env<\/jats:italic>population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.<\/jats:p>","DOI":"10.1128\/aac.01055-08","type":"journal-article","created":{"date-parts":[[2008,12,16]],"date-time":"2008-12-16T02:12:18Z","timestamp":1229393538000},"page":"1116-1123","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Virologic Failure in First-Line Human Immunodeficiency Virus Therapy with a CCR5 Entry Inhibitor, Aplaviroc, plus a Fixed-Dose Combination of Lamivudine-Zidovudine: Nucleoside Reverse Transcriptase Inhibitor Resistance Regardless of Envelope Tropism"],"prefix":"10.1128","volume":"53","author":[{"given":"James F.","family":"Demarest","sequence":"first","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Amrine-Madsen","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Irlbeck","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn M.","family":"Kitrinos","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msh196"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.657"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/431519"},{"key":"e_1_3_2_5_2","unstructured":"An evaluation of tropism profiles and other characteristics among 3988 individuals screened for the A4001026 A4001027 (MOTIVATE 1) and A4001028 (MOTIVATE 2) studies for maraviroc 2006"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(98)00062-X"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1177\/135965350801300204","volume":"13","year":"2008","unstructured":"Currier, J., A. Lazzarin, L. Sloan, N. Clumeck, J. Slim, D. McCarty, H. Steel, J.-P. Kleim, T. Bonny, and J. Millard, on behalf of the ASCENT Study Team. 2008. Antiviral activity and safety of aplaviroc with lamivudine\/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study. Antivir. Ther.13:297-306.","journal-title":"Antivir. Ther."},{"key":"e_1_3_2_8_2","unstructured":"HIV envelope tropism in treatment naive and experienced subjects 2004"},{"key":"e_1_3_2_9_2","unstructured":"873140 exhibits potent antiviral activity against a broad panel of HIV-1 envelopes from treatment naive and experienced subjects 2005"},{"key":"e_1_3_2_10_2","unstructured":"A novel CCR5 antagonist 873140 exhibits potent in vitro anti-HIV activity 2004"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/155.2.909"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.2.181"},{"key":"e_1_3_2_13_2","unstructured":"Late virologic breakthrough in treatment naive patients on a regimen of combivir + vicriviroc 2006"},{"key":"e_1_3_2_14_2","unstructured":"Virological correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-naive patients 2008"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/155.4.2011"},{"key":"e_1_3_2_16_2","first-page":"138","volume":"9","year":"1992","unstructured":"Hudson, R. R., D. D. Boos, and N. L. Kaplan. 1992. A statistical test for detecting geographic subdivision. Mol. Biol. Evol.9:138-151.","journal-title":"Mol. Biol. Evol."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2524.2005.00542.x"},{"key":"e_1_3_2_18_2","unstructured":"Clonal analysis of in vitro-derived viruses with reduced susceptibility to aplaviroc (873140 APL) shows wide range in IC50 and sequence changes 2005"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000183633.06580.8a"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.16.8654-8662.2004"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1086\/504693"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1086\/428096"},{"key":"e_1_3_2_23_2","first-page":"254","year":"1987","unstructured":"Nei, M. 1987. DNA polymorphism within and between populations, p. 254-286. InMolecular evolutionary genetics. Columbia University Press, New York, NY.","journal-title":"Molecular evolutionary genetics."},{"key":"e_1_3_2_24_2","first-page":"14","volume":"4","year":"1997","unstructured":"Nicholas, K. B., H. B. Nicholas, Jr., and D. W. Deerfield II. 1997. GeneDoc: analysis and visualization of genetic variation. EMBNEW News4:14.","journal-title":"EMBNEW News"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00821-07"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.4.920-928.2000"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/14.9.817"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000131310.52526.c7"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btg359"},{"key":"e_1_3_2_30_2","unstructured":"PAUP* phylogenetic analysis using parsimony (* and other methods) (4.0b10) 1998"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.24.4876"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.012519099"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02006-06"},{"key":"e_1_3_2_34_2","unstructured":"Analysis of baseline enfuvirtide (T-20) susceptibility and coreceptor tropism in two phase III study populations 2007"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00853-06"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1086\/511035"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01055-08","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01055-08","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T23:22:21Z","timestamp":1684797741000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01055-08"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,3]]}},"alternative-id":["10.1128\/AAC.01055-08"],"URL":"https:\/\/doi.org\/10.1128\/aac.01055-08","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3]]},"assertion":[{"value":"2008-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-11-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-03-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}