The once-weekly HIV pill just got harder to imagine. Twice.
Gilead Sciences announced this week that it is placing the WONDERS-1 and WONDERS-2 Phase 2/3 trials of GS-1720, an investigational integrase inhibitor, combined with GS-4182, an investigational capsid inhibitor and prodrug of lenacapavir, on clinical hold. The FDA identified a safety signal: decreases in CD4+ T-cell and absolute lymphocyte counts in a subset of participants receiving the combination. Gilead confirmed the hold in a company statement and said it is working with regulators to resolve the issues. As of the company's most recent earnings call, the holds remain in effect.
This is not a surprise setback. It is the second time in under a year that a major long-acting HIV program has run into an unexpected safety wall.
GSK, working with ViiV Healthcare, halted its Phase 2 oral integrase inhibitor VH3739937 in October 2024 after a safety signal emerged. That program was distinct from Cabenuva, GSK's injectable twice-yearly HIV therapy, which remains on the market and continues to generate positive data, including results from the LATITUDE/NET trial published in the New England Journal of Medicine in February 2026. Both GSK and Gilead were chasing the same goal: displacing the market-leading once-daily pill Biktarvy, Gilead's $14.3 billion-a-year combination therapy, with something patients would only need to take once a week.
The goal was not trivial. Daily oral therapy transformed HIV from a death sentence into a manageable chronic condition, and Biktarvy set a high bar: potent, well-tolerated, and taken as a single tablet once daily. Any successor had to match that tolerability profile while reducing the pill burden. That turned out to be a harder problem than the field anticipated.
According to Reuters, Evan Seigerman, an analyst at BMO Capital Markets, said "today's update underscores the difficulties of improving upon the profile of Gilead once-daily Biktarvy" after the clinical hold was announced last June.
The irony is that lenacapavir itself, the backbone of Gilead's weekly pill candidate, was Science's 2024 Breakthrough of the Year. As a twice-yearly injectable, marketed as Yeztugo, it posted a 100 percent efficacy rate in a large Phase 3 trial in women and girls in South Africa and Uganda, a result that stopped transmissions in the trial arm. Gilead CEO Daniel ODay called it one of the most important scientific breakthroughs of the company's history. Yet converting that injectable success into a weekly oral pill proved intractable.
The safety signal that triggered the clinical hold involves drops in CD4+ T-cells and lymphocytes. That is precisely the kind of immune suppression that HIV drugs exist to prevent. In the context of treating an immune-targeting virus, it is not a tolerability problem. It is a fundamental mechanism failure.
GS-1720 and GS-4182 are investigational agents and have not been approved anywhere globally. Both trials remain on clinical hold as of the most recent public update from the company.
What this moment reveals is that the long-acting HIV field made a strategic bet on convenience that the underlying biology has so far declined to honor. Both major programs ran into safety signals that were not anticipated from preclinical models. The immune system of people living with HIV is already under pressure. Adding a compound that further depletes key immune cells, even in a subset of participants, is a reason to stop, not a manageable side effect.
The bet may not be dead permanently. Long-acting HIV therapy remains a real clinical need for patients who struggle with daily adherence, and injectable twice-yearly lenacapavir has already proven that duration can be extended. But the oral weekly path, easier to manufacture, distribute, and take, just got significantly narrower. The two largest drugmakers in HIV have each spent years and considerable resources learning the same lesson: HIV is not a problem that gets easier when you try to make the pill less frequent.
The question now is who, if anyone, tries again.
† Add ‡ footnote: "Gilead has reported these efficacy results; the 100% figure has not been independently verified by endpoints.news."
† Add ‡ footnote: "Gilead has reported these efficacy results; the 100% figure has not been independently verified by endpoints.news."
