DAWNING is a non-inferiority study comparing dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) with a WHO-recommended regimen of lopinavir/ritonavir (LPV/r) + 2 NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2 NRTIs (ClinicalTrials.gov: NCT02227238).
Subjects were randomised (1:1, stratified by plasma HIV-1 RNA and number of fully active NRTIs) to 52 weeks of open-label treatment with DTG or LPV/r combined with 2 investigator-selected NRTIs, including at least one fully active NRTI based on Screening resistance testing. The primary endpoint was the proportion of subjects achieving HIV‑1 RNA <50 c/mL at Week 48 (Snapshot algorithm) with an interim analysis at Week 24. Post-hoc efficacy analyses were performed based on whether WHO-recommended second-line NRTIs were chosen per subjects’ first-line NRTIs; 59 subjects not taking WHO-recommended first-line NRTIs were excluded.
Of 968 subjects screened, only 78 (8%) were screen failures due to not having one fully active NRTI available; 624 were randomised and treated. At Week 24, DTG+2NRTIs was superior to LPV/r+2NRTIs, with 82% (257/312) and 69% (215/312) of subjects, respectively, achieving HIV-1 RNA <50 c/mL (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p<0.001). The difference was mainly driven by lower rates of Snapshot virologic non-response in the DTG group. 56% (347/624) of subjects received WHO-recommended second-line NRTIs, and their response rates within each arm were higher than those for subjects who did not. Regardless of WHO-recommended NRTI use, response rates were higher with DTG versus LPV/r-based regimens (Table). The overall safety profile of DTG+2NRTIs was favourable compared to LPV/r+2NRTIs with more drug-related adverse events reported in the LPV/r group. In this analysis, there were no treatment-emergent primary integrase-strand transfer inhibitor or NRTI resistance mutations in the DTG group through the randomisation phase.
In DAWNING, response rates were highest in subjects receiving DTG + WHO-recommended second-line NRTIs. Further, within each arm, subjects had higher response rates when receiving WHO-recommended versus other second-line NRTIs suggesting resistance testing to guide NRTI selection may not be necessary in this population. DAWNING provides important information to help guide second-line treatment decisions in resource-limited settings.