Background: DAWNING is a non-inferiority study comparing DTG+2NRTIs with a current WHO-recommended regimen of LPV/r+2NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non-nucleoside reverse transcriptase inhibitor + 2 NRTIs ( NCT02227238). Prior to a 24-week interim analysis, the Independent Data Monitoring Committee (IDMC) recommended discontinuation of the LPV/r arm due to superior efficacy of DTG+2NRTIs based on available data; the study protocol was amended to allow ongoing LPV/r subjects to switch to the DTG arm.
Methods: Subjects were randomised (1:1, stratified by Screening 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).
Results: 624 adults were randomized and treated. Subjects were well matched for demographic and baseline characteristics. The IDMC decision had limited impact on the primary endpoint as all LPV/r subjects who switched or discontinued due to the IDMC decision had a viral load value at Week 48/52. At Week 48, 84% (261/312) of subjects on DTG versus 70% (219/312) on LPV/r achieved HIV-1 RNA < 50 c/mL (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p < 0.001 for superiority). The difference was primarily driven by lower rates of Snapshot virologic non-response (VL ≥50 c/mL) in subjects on DTG. 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. Of 11 DTG subjects who met protocol-defined virologic withdrawal criteria through Week 52, one had treatment-emergent primary integrase-strand transfer inhibitor (INSTI) and NRTI resistance mutations while another had INSTI mutations only; in comparison, 30 LPV/r subjects met virologic withdrawal criteria, and 3 had emergent NRTI but no protease inhibitor mutations.

Week 48 outcomesDTG (N=312)LPV/r (N=312)
Snapshot virologic success261 (84%)219 (70%)
Snapshot virologic non-response30 (10%)68 (22%)
Data in window not <50 c/mL18 (6%)34 (11%)
Discontinued for lack of efficacy6 (2%)20 (6%)
Discontinued for other reason while not <50 c/mL or change in ART6 (2%)14 (4%)
Snapshot no virologic data21 (7%)25 (8%)
Discontinued due to AE or death7 (2%)17 (5%)
Discontinued for other reasons or missing data during window but on study14 (4%)8 (3%)
Drug-related AEs50/314 (16%)119/310 (38%)
[Week 48 outcomes]

Conclusions: In DAWNING, DTG+2NRTIs demonstrated superior efficacy at Week 48 and a favourable safety profile compared with LPV/r+2NRTIs confirming interim 24-week results. The study provides important information to help guide second-line treatment decisions in resource-limited settings.

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