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

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.

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.

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.

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.