Background:
Doravirine (DOR), an approved NNRTI, and Islatravir (ISL), an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), have complementary mechanisms of action and resistance profiles. We report week 48 results from a phase 3, open-label, non-inferiority trial (P017, NCT04223778) evaluating a switch from oral combination ART to DOR/ISL (100/0.75mg), a once-daily single-tablet regimen.
Methods:
Virologically suppressed adults on any stable oral 2- or 3-drug ART for ≥3 months with no history of treatment failure or virologic resistance to DOR were randomized (1:1) to switch to DOR/ISL or continue baseline ART (bART), stratified by bART regimen (PI-based, InSTI-based, Other). The primary endpoint was % of participants (pts) with HIV-1 RNA ≥50 c/mL at week 48 (FDA Snapshot; non-inferiority margin 4%). Resistance was assessed in pts with clinically significant confirmed viremia (CSCV; 2 consecutive measures of HIV-1 RNA ≥200 c/mL).
Results:
672 pts were randomized and treated with open-label DOR/ISL (n=336) or bART (n=336); 37% were female, 27% Black, mean age 45.5 (±11.7) years. bART was PI-based in 14%, InSTI-based in 52%, and Other (mainly NNRTI-based) in 34%; mean duration before study 39.4 months. At week 48, 0% on DOR/ISL and 1.5% on bART had HIV-1 RNA ≥50 c/mL (difference -1.5; 95%CI -3.4, -0.3), while 95.2% and 94.3% respectively had HIV-1 RNA < 50 c/mL (Table). CSCV occurred in 3 pts (1%) on bART (1 InSTI-based; 2 NNRTI-based), all had resistance to ≥1 component of their regimen. Mean change from baseline in CD4+ T-cell count at week 48 was -30.3 and +38.8 cells/mm3 for DOR/ISL and bART, respectively (difference ‑66.7, 95%CI -95.8, -37.7). Total lymphocyte count was also significantly reduced in the DOR/ISL group (Table). Rates of drug-related adverse events (AEs) (19.6%, 8.9%) and discontinuation due to AEs (2.1%, 0.3%) were higher in the DOR/ISL group. Rates of Grade 3-4 AEs (6.8%, 7.4%) and serious AEs (4.2%, 3.9%) were similar between groups. One death occurred (in bART group) due to motor vehicle accident. Infection rates were comparable between treatment groups (33.6% each) and no CDC AIDS-defining Category C events occurred.
Conclusions:
Switching to DOR/ISL (100/0.75mg) was non-inferior to continuing bART for maintaining viral suppression at week 48 and was generally well tolerated. No virologic failure was observed with DOR/ISL. Decreases in CD4+ T-cells and total lymphocytes with DOR/ISL were not associated with differences in infection-related AEs.
Table. Selected Efficacy & Safety Outcomes, DOR/ISL (100/0.75mg) P017