{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:37Z","timestamp":1772169157850,"version":"3.50.1"},"reference-count":30,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["64787"],"award-info":[{"award-number":["64787"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001342","name":"Department of Science and Technology, Republic of South Africa","doi-asserted-by":"publisher","award":["64787"],"award-info":[{"award-number":["64787"]}],"id":[{"id":"10.13039\/501100001342","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008196","name":"M\u00e9decins Sans Fronti\u00e8res","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["212265, 203135, 214321"],"award-info":[{"award-number":["212265, 203135, 214321"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE).\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load &lt;50 copies\/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:<\/ns4:bold>\n                    Impaired viral fitness due to NRTI resistance mutations and dolutegravir\u2019s high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy\u2019s early virologic efficacy with and without a supplementary dolutegravir dosing.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Registration:<\/ns4:bold>\n                    ClinicalTrials.gov\n                    <ns4:ext-link xmlns:ns5=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns5:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03991013?term=NCT03991013&amp;draw=2&amp;rank=1\">NCT03991013<\/ns4:ext-link>\n                    (19\/06\/2019).\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.16597.1","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T10:49:44Z","timestamp":1613558984000},"page":"33","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7872-0954","authenticated-orcid":false,"given":"Ying","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Keene","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-2878","authenticated-orcid":false,"given":"Rulan","family":"Griesel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaneez","family":"Sayed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zimasa","family":"Gcwabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olina","family":"Ngwenya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Schutz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rene","family":"Goliath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tali","family":"Cassidy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Goemaere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-6606","authenticated-orcid":false,"given":"Gary","family":"Maartens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme","family":"Meintjes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2021,2,17]]},"reference":[{"key":"ref-1","article-title":"Global 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.18291.r50587, Stephen Ian Walimbwa, Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda, 30 May 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-33\/v1#referee-response-50587","order":0,"name":"referee-response-50587","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18291.r51752, Laura Waters, Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK, 11 Aug 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-33\/v1#referee-response-51752","order":1,"name":"referee-response-51752","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18291.r42692, Loice Achieng Ombajo, Department of Clinical Medicine and Therapeutics, University of Nairobi, Nairobi, Kenya, 11 Aug 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-33\/v1#referee-response-42692","order":2,"name":"referee-response-42692","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This trial is supported by the Wellcome Trust [212265, <a href=https:\/\/doi.org\/10.35802\/212265>https:\/\/doi.org\/10.35802\/212265<\/a>], an Investigator Award to Professor Gary Maartens, and the M\u00e9decins Sans Fronti\u00e8res Khayelitsha project. The Wellcome Centre for Infectious Diseases Research in Africa is supported with core funding from the Wellcome Trust [203135, <a href=https:\/\/doi.org\/10.35802\/203135>https:\/\/doi.org\/10.35802\/203135<\/a>]. GrM is supported by the Wellcome Trust [214321, <a href=https:\/\/doi.org\/10.35802\/214321>https:\/\/doi.org\/10.35802\/214321<\/a>], and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa [64787]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}