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. In virologically suppressed adults, switching to DOR/ISL (100mg/0.75mg) was non-inferior to continuing prior antiretroviral regimens. We report week 48 results from a double-blind non-inferiority trial (NCT04233879) evaluating initial HIV-1 treatment with DOR/ISL (100mg/0.75mg) compared to B/F/TAF.
METHODS: Antiretroviral treatment-naïve adults with HIV-1 were randomized (1:1) to once-daily oral DOR/ISL (100mg/0.75mg) or B/F/TAF, stratified by screening CD4 count (</=200 cells/mm3) and HIV-1 RNA (=/>100,000 copies/mL). The primary efficacy endpoint was HIV-1 RNA <50 copies/mL at week 48 (FDA Snapshot approach, non-inferiority margin 10%, planned N=680). Due to exposure-related reductions in CD4+ T-cells and total lymphocytes, enrollment was closed before full accrual.
RESULTS: Of 599 randomized participants, 597 were treated with DOR/ISL (n=298) or B/F/TAF (n=299); mean age 35.2 years, 25% female, 29% Black, 20% had pre-treatment CD4 count <200 cells/mm3 and 19% had pre-treatment HIV-1 RNA >100,000 copies/mL. At week 48, 88.9% receiving DOR/ISL and 88.3% receiving B/F/TAF had HIV-1 RNA <50 copies/mL. Virologic failure (2 consecutive HIV-1 RNA =200 copies/mL) occurred in one DOR/ISL participant (with acquired resistance-associated mutations to DOR, due to non-adherence) and 4 B/F/TAF participants. Mean increase from baseline in CD4+ T-cell count was 182 cells/mm3 for DOR/ISL and 234 cells/mm3 for B/F/TAF. The treatment groups had similar mean weight gain (table) and similar rates of drug-related adverse events (AEs) and infection-related AEs (table). Discontinuation due to AE was higher for DOR/ISL (7.4% vs 3.3%) due to protocol-required discontinuations for decreased CD4 or total lymphocyte counts.
CONCLUSIONS: DOR/ISL (100mg/0.75mg) was non-inferior to B/F/TAF for initial treatment of HIV-1 and was generally well-tolerated. There were small treatment differences in CD4+ T-cell and lymphocyte count changes, with similar rates of infection-related AEs observed.