Background
Doravirine (DOR), an NNRTI, and islatravir (ISL), an investigational nucleoside reverse transcriptase translocation inhibitor, have complementary mechanisms of action and resistance profiles. MK-8591A-052 is an ongoing phase 3 study evaluating the efficacy and safety of switching from bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) to DOR/ISL (100/0.25 mg), a once-daily single-tablet regimen. Declines in CD4 T-cell and lymphocyte counts were seen with higher ISL doses.
Methods
In this double-blind, non-inferiority study (NCT05630755) adults with HIV-1, virologic suppression for ≥3 months on BIC/FTC/TAF, and no history of treatment failure or known resistance to DOR were randomized (2:1) to switch to DOR/ISL (100/0.25 mg) or continue BIC/FTC/TAF. Primary efficacy endpoint was % of participants with HIV-1 RNA ≥50 c/mL at week 48 (FDA snapshot; non-inferiority margin 4%). Discontinuation was required for confirmed decline in total lymphocytes (≥30% and to <1.0 x 109/L) or in CD4 T-cell count (≥30% and to <350 cells/mm3 from baseline ≥350 or to <200 from baseline ≤349).
Results
We treated 513 participants: 342 switched to DOR/ISL (100/0.25 mg), 171 continued BIC/FTC/TAF. Mean age was 47.6 (±12.9) yrs, 21.4% were female at birth, 60.8% were White, 30.8% were Black/African American, and 22.8% were Latine. At week 48, HIV-1 RNA was ≥50 c/mL in 5 (1.5%) participants on DOR/ISL and 1 (0.6%) on BIC/FTC/TAF (difference 0.9%, 95% CI -1.9, 2.9; CI upper bound <4%), demonstrating non-inferiority of DOR/ISL to BIC/FTC/TAF. HIV-1 RNA was <50 c/mL in 91.5% of participants on DOR/ISL and 94.2% on BIC/FTC/TAF. One participant on DOR/ISL discontinued due to lack of efficacy with no on-treatment resistance detected at the time of viremia. Rates of AEs (74.6% DOR/ISL, 71.3% BIC/FTC/TAF), drug-related AEs (10.2%, 9.4%), and discontinuations due to AEs (2.9%, 1.8%) were similar between groups. There were no between‑group differences in mean change in CD4 T-cell or total lymphocyte count at week 48. Two participants on DOR/ISL (0.6%) and one on BIC/FTC/TAF (0.6%) discontinued due to decrease in CD4 T-cell or total lymphocyte count.
Conclusions
DOR/ISL (100/0.25 mg) maintained viral suppression and was non-inferior to BIC/FTC/TAF at week 48. DOR/ISL was well tolerated with a similar safety profile to BIC/FTC/TAF and did not adversely affect lymphocytes.