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Clinical Trial
. 2026 Feb 4;81(6):e568-e580.
doi: 10.1093/cid/ciaf346.

A Randomized Trial to Compare Dolutegravir Plus Boosted Darunavir Versus Recommended Standard of Care Antiretroviral Regimens in People With HIV-1, Whose First-line Non-nucleoside Reverse Transcriptase Inhibitor Therapy Has Failed: Final 96-week Results of the D2EFT Study

Phyo Pyae Nyein  1 , Margaret Borok  2 , Nnakelu Eriobu  3 , Richard Kaplan  4 , Nagalingeswaran Kumarasamy  5 , Anchalee Avihingsanon  6 , Marcelo H Losso  7 , Iskandar Azwa  8 , Muhammad Karyana  9 , Sounkalo Dao  10 , Mohamed Cisse  11 , Jaime F Andrade Villanueva  12 , Sergio Lupo  13 , Sandra Wagner Cardoso  14 , Evy Yunihastuti  15 , Yanri Wijayanti Subronto  16 , Munawaroh Fitriah  17 , Sudirman Katu  18 , Dannae Brown  19 , Emmanuelle Papot  1 , Jolie Hutchinson  1 , Anthony Kelleher  1 , Josh Hanson  1 , Nila J Dharan  1 , Kathy Petoumenos  1 , Gail V Matthews  1 ; D2EFT Study Team
Collaborators, Affiliations
Clinical Trial

A Randomized Trial to Compare Dolutegravir Plus Boosted Darunavir Versus Recommended Standard of Care Antiretroviral Regimens in People With HIV-1, Whose First-line Non-nucleoside Reverse Transcriptase Inhibitor Therapy Has Failed: Final 96-week Results of the D2EFT Study

Phyo Pyae Nyein et al. Clin Infect Dis. .

Abstract

Background: Longer-term outcome data following second-line antiretroviral therapy initiation in resource-limited settings is limited, especially in regions where genotypic resistance is inaccessible. This analysis evaluated extended efficacy and tolerability data from the D2EFT study.

Methods: D2EFT is a completed, multicenter, phase IIIB/IV, randomized, open-label trial in 14 low- and middle-income countries. People with human immunodeficiency virus (HIV) who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to 1 of ritonavir-boosted darunavir plus 2 nucleoside reverse transcriptase inhibitors (DRV/r + 2NRTIs), ritonavir-boosted darunavir plus dolutegravir (DTG + DRV/r), or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG + TDF/XTC), with or without pre-switch genotyping. Here we report virological suppression at 96 weeks, defined as HIV RNA <50 copies/mL in a modified intention-to-treat population.

Results: Between November 2017 and January 2022, 1190 participants were screened, 828 were randomized, and 826 were included in the analysis. At week 96, the proportions of participants with HIV RNA <50 copies/mL were 191/251 (76.1%) in DRV/r + 2NRTIs, 215/251 (85.7%) in DTG + DRV/r, and 231/283 (81.6%) in DTG + TDF/XTC. The treatment differences (95% confidence intervals [CIs]) in proportions achieving virological suppression were 9.6% (2.7, 16.4) in DTG + DRV/r and 9.0% (1.4, 16.6) in DTG + TDF/XTC, compared to DRV/r + 2NRTIs. Intermediate or high-level dolutegravir resistance was identified in 3/27 (13%) of virological failures in individuals taking DTG + TDF/XTC but in no one taking DTG + DRV/r. No darunavir resistance was observed.

Conclusions: After 96 weeks of follow-up, DTG + DRV/r and DTG + TDF/XTC demonstrated virological superiority over DRV/r + 2NRTIs after first-line NNRTI-failure. However, emerging dolutegravir resistance, which was observed only in individuals taking DTG + TDF/XTC, requires ongoing global surveillance.

Keywords: RCT; antiretroviral therapy; developing countries; dolutegravir; second-line.

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Conflict of interest statement

Potential conflicts of interest. G. V. M. received grants for the present manuscript from the NIH and the Australian National Health and Medical Research Council (NHMRC), ViiV and Janssen, paid to their institution. G. V. M. has participated on an advisory board for ViiV Healthcare and AstraZeneca, received support for speakers bureau from ViiV, Gilead, and Pfizer, and is the Chair of STRIVE International Global Trials network. A. K. received Unitaid, ViiV, and NIH grants paid to their institution as well as institutional support from Merck Advisory Board and is the Chair and member of Scientia Clinical Research Board, with no renumeration. N. K. received funding from the University of New South Wales (UNSW) for the conduct of D2EFT study paid to their institution. M. L. received UNSW research grant for the present manuscript paid to their institution and Gilead and ViiV research grants paid to their institution. J. A. received support for the current manuscript from Fundacion IBIS-CICAL and grants, consulting fees from GlaxoSmithKline Mexico, and support for attending meetings from Fundacion Huesped de Argentina. N. D. received an unrestricted grant from Gilead Sciences Pty Ltd. K. P. received ViiV and Gilead Sciences grants paid to their institution. D. B. is an employee of ViiV Healthcare and holds GSK stock options. All other authors report no potential conflicts.

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