by Carolyn Chu, MD, MSc, AAHIVS, AAHIVM Chief Medical Officer

June 4, 2024

Featured Literature:

D2EFT Study Group. Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomized, phase 3b/4 trial. Lancet HIV. 2024 May 21: S2352-3018(24)00089-4. doi: 10.1016/S2352-3018(24)00089-4. PMID: 38788744   

The international D2EFT Study, originally designed to compare the NRTI-sparing dual regimen of ritonavir-boosted darunavir plus dolutegravir with standard of care, second-line boosted darunavir plus 2 NRTIs, subsequently added a third arm using dolutegravir plus fixed recycled NRTIs (TDF + XTC). This analysis describes one-year outcomes among 826 participants. Baseline resistance was evaluated for 737 participants: 675/720 (93%) had high-level resistance to at least one NRTI and 711/726 (98%) had high-level resistance to at least one NNRTI. One patient randomized to DRV/r plus DTG had S147SG. At week 48, 194/257 (75%) participants on DRV/r plus 2 NRTIs had VL less than 50 copies/mL vs. 222/264 (84%) among participants on DRV/r plus DTG vs. 227/291 (78%) among participants on DTG + TDF + XTC. Both intervention groups met non-inferiority criteria against standard of care, and DRV/r plus DTG also met superiority criteria. Fifteen individuals discontinued their study regimen for toxicity reasons and one case of acute hepatitis B infection occurred in a participant receiving DRV/r plus DTG. Resistance testing was performed on all samples with VL greater than 1000 copies/mL and available sequence data (n=53 for INSTI and n=47 for PI and RT). No DRV-associated mutations were observed. DTG-associated mutations were observed in one patient on DRV/r plus DTG (G118R) and three participants on DTG + TDF + XTC (one with G118R, two with R263K).

Author’s Commentary:

Results from this study have the potential to be highly impactful in both resource limited and resource rich settings – not only for programmatic decisions regarding second-line therapy options, but also for informing HIV drug resistance monitoring (particularly among treatment-experienced people who have been transitioned or are being considered for transition to a dolutegravir-based regimen). Despite high rates of NRTI resistance at baseline, the majority of participants receiving a dual NRTI backbone (plus either boosted darunavir or dolutegravir) achieved viral load suppression at one year. Additional follow-up will be particularly helpful to assess longer term outcomes for people who acquire INSTI-associated mutations on dolutegravir.

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