A phase 2 trial with 104 HIV-positive adults demonstrated that once-weekly islatravir (2mg) plus lenacapavir (300mg) maintained viral suppression as effectively as the current daily standard bictegravir/emtricitabine/tenofovir combination. At 24 weeks, 94.2% of participants in both groups achieved undetectable viral loads below 50 copies/mL, with only one treatment failure in the weekly regimen group versus none in the daily group. This non-inferiority persisted through 48 weeks of follow-up. The development represents a potentially transformative shift in HIV management, addressing one of the most persistent challenges in treatment adherence. Long-acting therapies could dramatically improve quality of life for people living with HIV by reducing pill burden from 365 to just 52 doses annually. However, the small study size and open-label design limit definitive conclusions. The weekly regimen's real-world performance remains uncertain, particularly regarding forgiveness for missed doses and long-term resistance patterns. While promising, larger phase 3 trials across diverse populations will be essential to establish whether weekly dosing can truly match the proven durability and safety profile of established daily regimens that have transformed HIV from fatal to manageable.