DAWNING is a non-inferiority study comparing dolutegravir (DTG) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) with 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 + 2 NRTIs.
Subjects were randomised (1:1, stratified by Screening HIV-1 RNA and number of fully active NRTIs) to 52 weeks of open-label treatment with DTG or LPV/r + 2 investigator-selected NRTIs, including at least one fully active NRTI based on Screening resistance testing. The primary endpoint was the proportion of subjects with HIV‑1 RNA <50 c/mL at Week 48 (Snapshot algorithm). Post-hoc efficacy analyses were performed based on baseline NRTI resistance profile and NRTI use in the second-line background regimen (BR).
Of 624 subjects randomised and treated, 499 (80%) received <2 active NRTIs at baseline. Overall, 84% (261/312) of subjects on DTG versus 70% (219/312) on LPV/r achieved HIV-1 RNA <50 c/mL at Week 48 (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p<0.001 for superiority). This difference was consistent regardless of the use of <2 or 2 fully active NRTIs in the BR. NRTI resistance was present in 561 subjects (90%) at baseline, M184V/I (alone or plus additional NRTI resistance-associated mutations [RAMs]) in 513 (82%), K65R in 187 (30%), and ≥1 thymidine-analogue mutations (TAMs) in 152 subjects (24%). Of subjects with M184V/I alone or plus ≥1 NRTI RAMs, 430 subjects (84%) took lamivudine (3TC) or emtricitabine (FTC) as part of their BR. Tenofovir disoproxil fumarate (TDF) was included in BR in the presence of K65R in 15 subjects while 86 subjects with 1 or more TAMs took zidovudine (AZT). Among subjects receiving 3TC or FTC in the presence of M184V/I, 85% (187/220) of subjects on DTG versus 72% (152/210) on LPV/r had HIV-1 RNA <50 c/mL at Week 48 (difference 12.6%, 95% CI: 4.9% to 20.3%). High responses were also observed in the DTG arm, when AZT or TDF were included in the BR in the presence of TAMs or K65R, respectively; however, subject numbers in these subgroups were small (Table 1).
In DAWNING, response rates were high in subjects receiving DTG+2NRTIs regardless of pre-existing resistance to one of the NRTIs in the BR, including in subjects using 3TC or FTC in the presence of M184V/I. In WHO interim guidance on HIV treatment, DTG+2NRTIs is now a recommended second-line treatment option for patients failing an NNRTI-based regimen.