Ulonivirine (MK-8507), an experimental non-nucleoside reverse transcriptase inhibitor, has the potential to be a component of once-weekly oral HIV treatment. Merck tested ulonivirine plus its nucleoside reverse transcriptase translocation inhibitor islatravir as a weekly regimen, but the Phase II trial was halted ahead of schedule after some participants saw declines in their CD4 T-cell or total lymphocyte counts, attributable to a high dose of islatravir. Interim results showed that people with viral suppression who were randomized to switch from once--daily Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) to once-weekly ulonivirine plus islatravir maintained a viral load below 50. While overall adverse events rates were similar, people assigned to the experimental regimen had substantially larger CD4 cell and total lymphocyte decreases, which were reversible after treatment discontinuation. Ulonivirine itself has not been implicated in the white blood cell declines. A new Phase IIb trial of ulonivirine plus a safer low dose of islatravir is now underway.