A once-weekly oral antiretroviral therapy (ART) regimen with two nucleoside reverse transcriptase translocation inhibitors, islatravir and the investigational drug ulonivirine (ISL/ULO), maintained similar levels of viral suppression as daily oral bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), according to findings from a phase 2b trial presented at the annual AIDS 2026 meeting in Rio de Janeiro, Brazil. 

“Oral once weekly ART is an attractive option for many people living with HIV and could potentially improve adherence over daily regimens for some populations,” Anne F. Luetkemeyer, MD, professor of medicine at the University of California, San Francisco, told attendees. “These results support the initiation of the coming phase 3 SYMPHORIA studies that will evaluate a fixed-dose combination of once-weekly islatravir/ulonivirine in virologically suppressed people living with HIV.”

Bruce Richman, founder of the Prevention Access Campaign and its Undetectable = Untransmittable movement, suggested that the possibility of a once-weekly oral ART could be transformative for many people living with HIV.

“Taking a daily pill can make folks vulnerable to stigma, discrimination, and other harms,” Richman said. “Long-acting treatment is the new frontier, bringing great choice, freedom, and safety for people with HIV.”

The trial enrolled 157 adults with HIV who had no history of treatment failure, no known resistance-associated mutations linked to ULO, no active hepatitis B or C infection, and a CD4 cell count of at least 200 cell/mm³. Participants had a median CD4 cell count of 810 at baseline, and they had been on ART for a median of 10.6 years, including a median of 4.3 years specifically on BIC/FTC/TAF.

The participants included 71% cisgender men, 27% cisgender women, and 1.9% transgender women. They were a median of 48 years old, and nearly half (45%) were aged 50 years or older. A quarter were Hispanic/Latino (24%), and over half were White (55%), with 32% Black/African American, 6% Asian, and 7% multiracial/other participants. Most participants were from the US (69%), with others enrolled from Australia (18%) and Switzerland (13%).

Among the 74 participants assigned to switch to ISL/ULO, 94.9% maintained viral suppression at 24 weeks compared with 97.5% of the 77 participants who continued on BIC/FTC/TAF (-1.3% difference; 95% CI, -6.9 to 3.5). No virologic data were available for five participants. None of the participants taking ISL/ULO experienced a viral load greater than 50 copies/mL; one person taking BIC/FTC/TAF exceeded 50 copies/mL but was subsequently suppressed.

Overall adverse event rates were similar between ISL/ULO (55%) and BIC/FTC/TAF (56%), though there were more drug-related adverse events with ISL/ULO (13%) than with BIC/FTC/TAF (0%). All the drug-related adverse events were grade 1 or 2 and were expected because of the open-label switch design, Luetkemeyer said. One participant discontinued ISL/ULO, and none discontinued BIC/FTC/TAF.

There were no clinically meaningful differences in mean body weight change from baseline between the groups, and CD4 cell counts and total lymphocyte counts remained similar between the groups throughout the trial.

ISL/ULO trails one other investigational once-weekly oral ART regimen whose findings were also presented at the conference. The two phase 3 ISLEND trials, one open-label and one blinded, found that once-weekly oral islatravir/lenacapavir (ISL/LEN) maintained comparably high viral suppression rates when compared with BIC/FTC/TAF or to any nucleoside reverse transcriptase inhibitor (NRTI)-based standard-of-care regimen with an integrase strand transfer inhibitor, a non-NRTI, or a boosted protease inhibitor.

Those 48-week trials showed suppression rates of 93%-95% with ISL/LEN, similar to the 92%-95% rates of the daily oral ART regimens, and had average adherence rates of 99%. Those data will be submitted for regulatory approval by Gilead Sciences and Merck.

Richman emphasized the importance of clinicians discussing daily and long-acting options with their patients depending on each patient’s particular needs and circumstances.

“Clinicians should have open conversations about their patients’ lives, the potential benefits and challenges with daily and long-acting treatments, and, most importantly, ensure that choice of treatment is a shared decision,” Richman said.

The study was funded by Merck. Luetkemeyer reported receiving research grants from Merck, Gilead Sciences, and GSK/ViiV Healthcare and travel support from Merck. Richman had no disclosures.

Tara Haelle has covered science and medicine for nearly two decades and is the author of Vaccination Investigation: The History and Science of Vaccines and The Informed Parent: A Science-Based Resource for Your Child’s First Four Years. She is based in Dallas.