Doravirine Resistance Patterns Identified Through Week 192 in the DRIVE-FORWARD and DRIVE-AHEAD Phase 3 Clinical Trials

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) designed to address the limitations of other NNRTIs, particularly resistance due to common RT substitutions including K103N, Y181C, and G190A. METHODS: This report summarizes the development of genotypic and phenotypic resistance to doravirine through week 192 of the DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674) phase 3 studies in adults with previously untreated HIV-1. Participants were randomized (1:1) to the doravirine or comparator regimen (darunavir/ritonavir or efavirenz) for 96 weeks (double-blind phase), followed by 96 weeks of the doravirine regimen (open-label extension). Resistance was evaluated in participants with protocol-defined virologic failure (PDVF; nonresponse or rebound) or treatment discontinuation (d/c) for other reasons and HIV-1 RNA >400 copies/mL. RESULTS: Of 747 participants randomized to doravirine, 51 (34 PDVF, 17 d/c) met resistance-testing criteria. Doravirine resistance-associated mutations (RAMs) were detected in 12/51 participants, by week 48 in 9/12, with phenotypic resistance to doravirine in 10. Of 502 participants who switched from comparator to doravirine, 9 (6 PDVF, 3 d/c) met resistance-testing criteria: Doravirine RAMs were detected in 4/9, conferring phenotypic resistance to doravirine in 3. The most common doravirine RAMs were V106A/I/M and F227C. Common RAMs observed with other NNRTIs (K103N, Y181C, K101E, E138K, and G190A) were not detected in any participant who met resistance-testing criteria. CONCLUSIONS: In DRIVE-FORWARD and DRIVE-AHEAD, the development of resistance to doravirine was uncommon (genotypic 1.3%; phenotypic 1.0%) and occurred mainly during the first 48 weeks of treatment. Overall, the RAMs observed with doravirine were distinct from those of other NNRTIs.