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Background: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily (QD) dosing. In the phase 3 DRIVE-FORWARD study in HIV-1 treatment-naïve adults receiving 2 NRTIs, DOR 100mg QD was non-inferior to darunavir+ritonavir on efficacy, and demonstrated a more favorable lipid profile.
Methods: DRIVE- AHEAD compared doravirine with efavirenz (EFV) in an ongoing phase 3, multicenter, double-blind, non-inferiority trial. Eligible participants were antiretroviral treatment-naïve adults with HIV-1 infection and pre-treatment HIV-1 RNA ≥1,000 c/mL. Participants were randomized (1:1) to a once-daily fixed-dose regimen of DOR 100mg, lamivudine 300mg and tenofovir disoproxil fumarate 300mg (DOR/3TC/TDF) or EFV 600mg, emtricitabine 200mg and TDF 300mg (EFV/FTC/TDF) for up to 96 weeks. Randomization was stratified by screening HIV-1 RNA (≤/>100,000 c/mL) and hepatitis B/C co-infection (yes/no). Primary efficacy endpoint was % of participants with HIV-1 RNA < 50 c/mL at week 48 (FDA Snapshot approach). Predefined non-inferiority margin was 10%. Primary safety endpoint was % of participants with prespecified neuropsychiatric adverse events (dizziness, sleep disorders/disturbances, altered sensorium).
Results: Of 734 participants randomized, 728 received study drug (364 in each treatment group) and were included in the analyses (mean age 33 years, 85% male, 48% white). At week 48, HIV-1 RNA < 50 c/mL was achieved by 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients (difference 3.5%, 95%CI [-2.0, 9.0]). The incidence of dizziness, sleep disorders/disturbances, and altered sensorium (table) was lower in DOR/3TC/TDF recipients than in EFV/FTC/TDF recipients (p< 0.001, p< 0.001, and p=0.033, respectively). Fasting LDL-C and non-HDL-C (table) were reduced by DOR/3TC/TDF and increased by EFV/FTC/TDF (both p< 0.0001).
Conclusions: In HIV-1 treatment-naïve adults, the efficacy of DOR/3TC/TDF at week 48 was non-inferior to EFV/FTC/TDF and similar regardless of baseline HIV-1 RNA. DOR/3TC/TDF was generally safe and well tolerated, with significantly fewer neuropsychiatric events than EFV/FTC/TDF and a favorable lipid profile.

Week 48 Efficacy & Safety Outcomes
[Week 48 Efficacy & Safety Outcomes]