Papot, EmmanuelleJacoby, SimoneArlinda, DonaAvihingsanon, AnchaleeAzwa, IskandarBorok, MargaretBrown, DannaeCissé, MohamedDao, SounkaloEriobu, NnakeluKaplan, RichardKaryana, MuhammadKumarasamy, NagalingeswaranLee, JohnnieLosso, Marcelo H.Matthews, Gail V.Perelis, LeonardoPerez-Casas, CarmenRuxrungtham, KiatWatkins, MelyndaLane, H. CliffordKelleher, AnthonyLaw, MatthewPolizzotto, Mark N.2025-03-282025-03-28Scopus:85135551505PubMed:35938597https://dspace-test.anu.edu.au/handle/1885/733743508A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.AA, AK, CPC, DA, EP, GVM, HCL, IA, KR, LP, MB, MC, MK, MW, NE, NK, RK, SD and SJ declare none. DB is a full-time employee of ViiV Healthcare and is a GSK shareholder. JL is an employee of Janssen. MHL received research funding to institution from ViiV. MNP received research funding to institution from ViiV, Gilead, Janssen, Bristol Myers Squibb. ML declared unrestricted research grants from Gilead Sciences, Janssen-Cilag and ViiV Healthcare. for the D2EFT study is provided by Unitaid (grant number: 2016-09-UNSW), National Institutes of Health (grant numbers: 18Q065 and 19Q120), National Health and Medical Research Council (grant number: APP1104610), ViiV Healthcare; the study drugs in D2EFT (namely darunavir and dolutegravir) are a ViiV Healthcare and Janssen donation. The authors gratefully acknowledge the contribution of the D2EFT Study Group (present representatives: see list below, and deceased: Prof. David Cooper, Prof. James Gita Hakim and Dr. Ernest Ekong), of the other academic collaborators (Dr. H. Clifford Lane; NIH), institutional collaborators (WHO and CHAI) and funding partners (Unitaid, NIH, NHMRC and ViiV Healthcare), and community representatives (chair: Leonardo Perelis) who support the D2EFT study; companies which donated darunavir and dolutegravir (ViiV Healthcare and Janssen Pharmaceutica); and the participation of the patients, healthcare givers and researchers in D2EFT project. D2EFT Study group (alphabetical order for each sub-groups) The Kirby Institute : Eamon Brown, Michelle Burns, Ai Caldis, Cate Carey, Megan Clewett, David Cooper, Sean Emery, Yuvaraj Ghodke, Simone Jacoby, Anthony Kelleher, Matthew Law, Margaret Lowe, Gail V. Matthews, Emmanuelle Papot, Mark N. Polizzotto, David Silk. Protocol Steering Committee : Iskandar Azwa, Margaret Borok, Dannae Brown, Mohamed Ciss\u00E9, Sounkalo Dao, Nnakelu Eriobu, Simone Jacoby, Richard Kaplan, Muhammad Karyana, Anthony Kelleher, Nagalingeswaran Kumarasamy, H. Clifford Lane, Matthew Law, Johnnie Lee, Marcelo H. Losso, Gail V. Matthews, Leonardo Perelis, Carmen Perez-Casas, Mark N. Polizzotto, Kiat Ruxrungtham, Jean Van Wyk, Melynda Watkins. Country teams : Argentina (Patricia Burgoa, Marcelo H. Losso, Sergio Lupo, Luciana Peroni, Renzo Moretto, Ana Melisa Solari, Silvina Tavella, Maria Ines Vieni Deborah Vanina Villegas); Brazil (Kelly Gama, Beatriz Grinsztejn); Chile (Gladys Allendes, Marcelo Wolff); Colombia (Ana Julia Rojas, Otto Sussmann); Guinea (Mohamed Cisse, Thierno Mamadou Tounkara); India (Faith Beulah, Nagalingeswaran Kumarasamy, Poongulali Selvamuthu); Indonesia (Yusrina Adani, Dona Arlinda, Yufi Aulia Azmi, Usman Hadi, Sudirman Katu, Munawir Muhammad, Nur Herda Wati Nisa, Yanri Wijayanti Subronto, Evy Yunihastuti); Malaysia (Iskandar Azwa, Farhana Nadiah Abd Ghani, Chow Ting Soo, Margaret Tan); Mali (Sounkalo Dao, Yacouba Cissoko); Mexico (Jaime Andrade-Villanueva, Juan Luis Mosqueda G\u00F3mez, Fernando Amador Lara, Juan Sierra Madero, Sergio del Moral Ponce, Jorge Morales Varges); Nigeria (Maryam Al-Mujtaba, Peter Ekele, Nnakelu Eriobu); Thailand (Anchalee Avihingsanon, Ploenchan Chetchotisakd, Sivaporn Gatechompol, Suwimon Khusuwan, Weerawat Manosuthi, Supawadee Pongprapass, Kanitta Pussadee, Supeda Thongyen, Anchalee Tiyabut); South Africa (Desiree Van Amsterdam, Jaclyn Ann Bennet, Richard Kaplan, Lerato Mohapi, Suri Moonsamy, Mary Sihlangu); Zimbabwe (Margaret Borok, Ennie Chidziva-Chikuse).10EnglishPublisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.drug-sparing regimensfixed-dose combinationsHIVMAMSrandomised-clinical trialTLD202210.1080/25787489.2022.2103572http://www.scopus.com/inward/record.url?scp=85135551505&partnerID=8YFLogxK