{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:07:24Z","timestamp":1779203244553,"version":"3.51.4"},"reference-count":33,"publisher":"American Society for Clinical Investigation","issue":"19","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,17]]},"abstract":"<jats:p>The second-generation HIV-1 integrase strand transfer inhibitor (InSTI) dolutegravir (DTG) has had a major impact on the treatment of HIV-1 infection. Here we describe important but previously undetermined pharmacodynamic parameters for DTG. We show that the dose-response curve slope, which indicates cooperativity and is a major determinant of antiviral activity, is higher for DTG than for first-generation InSTIs. This steepness does not reflect inhibition of multiple steps in the HIV-1 life cycle, as is the case for allosteric integrase inhibitors and HIV-1 protease inhibitors. We also show that degree of independence, a metric of interaction favorability between antiretroviral drugs, is high for DTG and nucleoside reverse transcriptase inhibitors. Finally, we demonstrate poor selective advantage for HIV-1 bearing InSTI resistance mutations. Selective advantage, which incorporates both the magnitude of resistance conferred by a mutation and its fitness cost, explains the high genetic barrier to DTG resistance. Together, these parameters provide an explanation for the remarkable clinical success of DTG.<\/jats:p>","DOI":"10.1172\/jci.insight.90033","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T16:25:35Z","timestamp":1479313535000},"source":"Crossref","is-referenced-by-count":14,"title":["Quantitative evaluation of the antiretroviral efficacy of dolutegravir"],"prefix":"10.1172","volume":"1","author":[{"given":"Sarah B.","family":"Laskey","sequence":"first","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Siliciano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Howard Hughes Medical Institute, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2016,11,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(11)70290-0"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215541"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70257-3"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60084-2"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2015.1059818"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv197"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01881-15"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s12977-016-0265-x"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0022-5193(76)90169-7"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm1777"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2649"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67399"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1186\/1742-4690-10-57","article-title":"LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions","volume":"10","author":"Desimmie","year":"2013","journal-title":"Retrovirology"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.1186\/1742-4690-10-144","article-title":"Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage","volume":"10","author":"Le Rouzic","year":"2013","journal-title":"Retrovirology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074163"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300703110"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.551119"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/BF01952257"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-7348.1939.tb06990.x"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg100"},{"key":"B21","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1086\/505356","article-title":"Rationale and uses of a public HIV drug-resistance database","volume":"194 Suppl 1","author":"Shafer","year":"2006","journal-title":"J Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06591-11"},{"issue":"4 Suppl 3","key":"B23","article-title":"The R263K mutation in HIV integrase that is selected by dolutegravir may actually prevent clinically relevant resistance to this compound","volume":"17","author":"Wainberg","year":"2014","journal-title":"J Int AIDS Soc"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01615-1"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01522-15"},{"key":"B26","unstructured":"Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. AidsInfo. http:\/\/aidsinfo.nih.gov\/contentfiles\/lvguidelines\/AdultandAdolescentGL.pdf Updated July 14, 2016. Accessed October 21, 2016"},{"key":"B27","unstructured":"Sued OG, et al. Comparable viral decay in dual and triple dolutegravir-based antiretroviral therapy. Abstract presented at: CROI Conference; February 22\u201325, 2016; Boston, Massachusetts. http:\/\/www.croiconference.org\/sessions\/comparable-viral-decay-dual-and-triple-dolutegravir-based-antiretroviral-therapy Accessed October 21, 2016."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018360108"},{"key":"B29","doi-asserted-by":"crossref","DOI":"10.7448\/IAS.18.1.20824","article-title":"Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy","volume":"18","author":"Wainberg","year":"2015","journal-title":"J Int AIDS Soc"},{"issue":"1","key":"B30","doi-asserted-by":"crossref","first-page":"78","DOI":"10.32607\/20758251-2015-7-1-78-86","article-title":"Influence of drug resistance mutations on the activity of HIV-1 subtypes A and B integrases: a comparative study","volume":"7","author":"Shadrina","year":"2015","journal-title":"Acta Naturae"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3351"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.4.1718-1729.2004"},{"key":"B33","unstructured":"ViiV Healthcare Company. TIVICAY (Dolutegravir) prescribing information. https:\/\/www.gsksource.com\/pharma\/content\/dam\/GlaxoSmithKline\/US\/en\/Prescribing_Information\/Tivicay\/pdf\/TIVICAY-PI-PIL.PDF Accessed October 21, 2016"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/90033\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:22:16Z","timestamp":1779200536000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/90033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,17]]},"references-count":33,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2016,11,17]]},"published-print":{"date-parts":[[2016,11,17]]}},"alternative-id":["10.1172\/jci.insight.90033"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.90033","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,17]]},"article-number":"e90033"}}