Background:
In 2 phase 3 clinical trials, switching to the 2-drug combination doravirine/islatravir (DOR/ISL) 100/0.75mg was non-inferior to continuing the prior antiretroviral (ART) regimen. This exploratory post-hoc analysis examined the impact of pre-existing resistance-associated mutations (RAMs) on the virologic response to DOR/ISL in these trials, focusing on M184V/I and other RAMs in reverse transcriptase.
Methods:
MK8591A-017 (P017; NCT04223778) was an open-label study in adults receiving any oral 2- or 3-drug ART regimen. MK8591A-018 (P018; NCT04223791) was a double-blind study in adults receiving bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). Participants with HIV-1 RNA <50 copies/mL and no known treatment failure or DOR resistance at baseline were randomized (1:1) to switch to once-daily DOR/ISL (100/0.75mg) or to continue baseline ART (bART) in P017 or B/F/TAF in P018; at week 48, the P017 bART group switched to open-label DOR/ISL. RAMs present at baseline in HIV proviral DNA were identified by Monogram Bioscience (GenoSure Archive assay). Genotypic resistance analyses were based on IAS-USA drug resistance mutation lists for approved ART and other mutations reported in the scientific literature.
Results:
Baseline resistance data were available for ~90% of study participants (Table 1). Of the 889 participants who received DOR/ISL in P017 or P018 and had baseline resistance data available, 46 (5.2%) had M184M/I/V at baseline; none of these participants had confirmed viremia (CV; 2 consecutive HIV-1 RNA ≥200 copies/mL 2-4 weeks apart) or low-level viremia (LLV; 2 consecutive HIV-1 RNA ≥50 and <200 copies/mL 2-4 week apart) while receiving DOR/ISL, and 2/46 (4.3%) had ≥1 viral blips (HIV-1 RNA ≥50 copies/mL followed by <50 copies/mL at next measurement). Twenty participants (6.5%) in the bART group had M184M/I/V at baseline: 2/20 (10%) developed CV, and none had LLV or viral blips. Twelve participants (4.3%) in the B/F/TAF group had M184M/I/V at baseline: none developed CV or LLV, and 1/12 (8.3%) had ≥1 viral blips. NNRTI RAMs were present at baseline in 287 (32.3%) of 889 DOR/ISL participants, 100 (32.6%) bART participants, and 85 (30.4%) B/F/TAF participants. Among participants with NNRTI RAMs, virologic outcomes were similar in the DOR/ISL and comparator groups (Table 1).
Conclusions:
Switching to DOR/ISL 100/0.75mg maintains viral suppression for up to 96 weeks regardless of archived M184I/V or NNRTI RAMs in proviral DNA.
