A randomised 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; Margaret Borok; Nnakelu Eriobu; Richard Kaplan; Nagalingeswaran Kumarasamy; Anchalee Avihingsanon; Marcelo H Losso; Iskandar Azwa; Muhammad Karyana; Sounkalo Dao; Mohamed Cisse; Jaime F Andrade Villanueva; Sergio Lupo; Sandra Wagner Cardoso; Evy Yunihastuti; Yanri Wijayanti Subronto; Munawaroh Fitriah; Sudirman Katu; Dannae Brown; Emmanuelle Papot; Jolie Hutchinson; Anthony Kelleher; Josh Hanson; Nila J Dharan; Kathy Petoumenos; Gail V Matthews; DEFT Study Team

doi:10.1093/cid/ciaf346

A randomised 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

Clin Infect Dis. 2025 Jun 27:ciaf346. doi: 10.1093/cid/ciaf346. Online ahead of print.

Authors

Phyo Pyae Nyein¹, Margaret Borok², Nnakelu Eriobu³, Richard Kaplan⁴, Nagalingeswaran Kumarasamy⁵, Anchalee Avihingsanon⁶, Marcelo H Losso⁷, Iskandar Azwa⁸, Muhammad Karyana⁹, Sounkalo Dao¹⁰, Mohamed Cisse¹¹, Jaime F Andrade Villanueva¹², Sergio Lupo¹³, Sandra Wagner Cardoso¹⁴, Evy Yunihastuti¹⁵, Yanri Wijayanti Subronto¹⁶, Munawaroh Fitriah¹⁷, Sudirman Katu¹⁸, Dannae Brown¹⁹, Emmanuelle Papot¹, Jolie Hutchinson¹, Anthony Kelleher¹, Josh Hanson¹, Nila J Dharan¹, Kathy Petoumenos¹, Gail V Matthews¹; DEFT Study Team

Collaborators

Affiliations

¹ The Kirby Institute, University of New South Wales, Sydney, Australia.
² University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
³ Institute of Human Virology Nigeria, Abuja, Nigeria.
⁴ Desmond Tutu Health Foundation, Cape Town, South Africa.
⁵ Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS) Voluntary Health Services (VHS), Chennai, India.
⁶ HIV-NAT, Thai Red Cross AIDS and Infectious Disease Research Centre, and Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁷ CICAL, Fundación IBIS, Buenos Aires, Argentina.
⁸ Infectious Disease Unit, Department of Medicine and Centre of Excellence for Research in Infectious Diseases & AIDS (CERIA), Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
⁹ INA-RESPOND, Jakarta, Indonesia.
¹⁰ University Clinical Research Centre (UCRC), Bamako, Mali.
¹¹ Centre de traitement ambulatoire de Donka (Hospital de jour), Conakry, Guinea.
¹² Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Mexico.
¹³ Instituto CAICI, Rosario, Argentina.
¹⁴ Fiocruz-Instituto Nacional de Infectologia (INI), Rio de Janeiro, Brazil.
¹⁵ Cipto Mangunkusumo Hospital/Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
¹⁶ Department of Internal Medicine/Centre of Tropical Medicine Study Program, Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta, Indonesia.
¹⁷ Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga/Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
¹⁸ Department of Internal Medicine, Faculty of Medicine, Universitas Hasanuddin/Division of Tropical and Infection Disease, Dr. Wahidin Sudirohusodo Hospital, Makassar, South Sulawesi, Indonesia.
¹⁹ Global Medical Sciences, ViiV Healthcare, Abbotsford, Australia.

PMID: 40577173
DOI: 10.1093/cid/ciaf346

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 HIV who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to one of ritonavir-boosted darunavir plus two 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% 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.