Phase III treatment naive study: Doravirine non-inferior to darunavir/r at 48 weeks

Comment: Abstract follows:

Doravirine seeks to address the limitations of the currently available NNRTIs: avoidance of neuropsychiatric side effects, no food requirements or concerns re co-administration with antacids/PPIs, fewer drug-drug interactions and a once daily option with a higher genetic barrier to resistance than efavirenz or rilpivirine.

83.8% (321/383) of subjects on the doravirine arm had an undetectable viral load at week 48 when compared to the darunavir/r arm  79.9% (306/383). When comparing this to the phase II F/TAF/BIC versus F/TAF/DTG data presented earlier this session (97% and 91% respectively), I wonder what role doravirine will play in the treatment naïve setting. Ideally a treatment naïve phase III trial comparing doravirine to an integrase inhibitor such as dolutegravir would help to answer this question. 

Perhaps it will find a place as a once daily salvage option?

45LB DORAVIRINE IS NON-INFERIOR TO DARUNAVIR/R IN PHASE 3 TREATMENT-NAIVE TRIAL AT WEEK 48

Jean-Michel Molina et al

Background: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily dosing and potent in vitro activity against the most common NNRTI resistant variants (K103N, Y181C, G190A). In a phase 2b study, DOR 100 mg once daily (QD) demonstrated similar efficacy to efavirenz, with favourable safety and tolerability through Week 48.

Methods: DRIVE-FORWARD is an ongoing, phase 3, multicenter, double-blind, non-inferiority trial in antiretroviral treatment-naive adults with HIV-1 infection and pre-treatment HIV-1 RNA ≥1,000 c/mL. Participants were stratified by screening HIV-1 RNA (≤ or >100,000 c/mL) and investigator-selected NRTI backbone therapy (TDF/FTC or ABC/3TC) and randomized in a 1:1 ratio to receive DOR 100 mg QD or darunavir 800 mg with ritonavir 100 mg (DRV/r) QD, in combination with the selected NRTI, for up to 96 weeks. The primary endpoint was the proportion (%) of participants achieving HIV-1 RNA <50 c/mL at Week 48 (NC=F, FDA Snapshot approach) with predefined non-inferiority margin of 10%. A secondary objective was to evaluate the effects of DOR and DRV/r on fasting serum lipids.

Results: Of 769 participants randomized, 766 (383 in each group) received study drug and were included in the efficacy and safety analyses (mean age 35.2 years, 84% male, 73% white, 87% on TDF/FTC). DOR was non-inferior to DRV/r on the primary endpoint, with 83.8% (321/383) and 79.9% (306/383), respectively, achieving HIV-1 RNA <50 c/mL at Week 48 (difference 3.9%, 95% CI [-1.6, 9.4]). In the subgroup with baseline HIV-1 RNA >100,000 c/mL, 81.0% (64/79) on DOR and 76.4% (55/72) on DRV/r achieved HIV-1 RNA <50 c/mL at Week 48 (OF approach). Adverse event rates (overall, serious, drug-related, and leading to treatment discontinuation) were similar across treatment groups. The most common drug-related AEs (>5% in one or more treatment groups) were diarrhea (5.5%, 12.8%), nausea (6.5%, 7.6%), and headache (6.0%, 2.6%) for DOR and DRV/r, respectively. Fasting LDL-C and non-HDL-C were reduced by DOR and increased by DRV/r (see table) with statistically significant treatment differences (p<0.0001).

Conclusion: At Week 48, DOR demonstrated potent efficacy and was non-inferior to DRV/r on a background of 2 NRTIs in HIV-1 treatment-naive adults. Efficacy was similar regardless of baseline HIV-1 RNA. DOR was generally safe and well-tolerated with a superior lipid profile for fasting LDL-C and non-HDL-C compared to DRV/r.