Background:
Randomised comparative data on efficacy and safety of second-line antiretroviral (ARV) regimens, after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are limited.
Methods:
D2EFT is an international randomised open-label trial comparing dolutegravir (DTG) with ritonavir boosted darunavir (DRV/r) versus DTG with fixed tenofovir and lamivudine or emtricitabine (TDF/XTC) versus standard of care (SOC: DRV/r+2NRTIs with a rotation of nucleosides or in adaptation to HIV genotyping) in adults living with HIV-1 whose first-line NNRTI therapy has failed. The study initially compared DTG+DRV/r vs SOC (stage 1) but later added a third arm (DTG+TDF/XTC, stage 2). Study was designed to show non-inferiority against SOC in terms of HIV-RNA < 50c/mL at 48 weeks using a delta=12%. Primary outcome data are presented as modified intent to treat analysis including all available data.
Results:
831 participants from 14 countries across Asia, Africa and Latin America, were randomised: Stage 1 DTG+DRV/r (n=56) vs SOC (n=53); Stage 2 DTG+DRV/r (n=216) vs SOC (n=210) vs DTG+TDF/XTC (n=296). Median age was 55 years and 54% were female. Median CD4 was 206 cells/mm3 and median HIV-RNA was 4.2log10c/ml. First-line failing regimen was efavirenz based in 85%.At 48 weeks the percentage with HIV-RNA < 50c/ml in Stage 1 was 75.4% SOC vs 84.1% DTG+DRV/r; in Stage 2: 71.4% SOC, 84.7% DTG+DRV/r, 78.0% DTG+TDF/XTC. Compared to SOC, the % difference in HIV-RNA < 50c/ml was -8.6% (95% confidence interval; -15.5, -1.7, p=0.02) for DTG+DRV/r, and -6.7 (-14.4, 1.2, p=0.09) for DTG+TDF/XTC (Figure 1). 143/169 (85%) of virological failure was due to rebound.Mean CD4 gain to week 48 was significantly greater in both DTG+DRV/r (56.0 cells/mm3 (26.5, 85.5) p < 0.001) and DTG+TDF/XTC (39.9 cells/mm3 (9.6, 70.2) p=0.01) compared to SOC. 14 deaths (none treatment related) and 97 SAEs (14 possibly treatment related) occurred. 35 pregnancies (24 deliveries) occurred with no congenital defects. Compared to SOC, mean weight gain was greater in both DTG+DRV/r 2.7kg (1.5, 3.8kg, p < 0.001) and DTG+TDF/XTC 1.7kg (0.5, 2.9kg, p=0.006) arms.
Conclusions:
In failing NNRTI-based first-line ARV, a switch to either DTG+DRV/r or DTG+TDF/XTC, without universal access to genotyping, was non-inferior in achieving viral suppression compared to DRV/r+2NRTIs, with DTG+DRV/r also achieving superiority.
Undetectable HIV RNA at week 48 by randomised treatment arm