Islatravir-ulonivirine, another combination pill that could put HIV treatment on a weekly schedule | AIDS 2026

Once-weekly islatravir-lenacapavir was in the limelight today at AIDS 2026, the 26th International AIDS Conference, in Rio de Janeiro, Brazil. Positive results for islatravir-lenacapavir from two phase 3 trials were reported at two sessions, including one featuring research selected by the meeting’s co-chairs, and an article about the results of one of those trials was published simultaneously in the New England Journal of Medicine.

But another islatravir combination is making a bid to also be a more convenient, perhaps less costly weekly alternative to daily antiretroviral pills, although it has a checkered past that may now be put to rest with a lower dose of islatravir.

Results of an open-label phase 2b study of a once-weekly combination pill that includes 2 milligrams (mg) of islatravir and 200 mg of ulonivirine presented at the meeting today showed the islatravir-ulonivirine combination was similarly effective as daily pills containing bictegravir, emtricitabine and tenofovir alafenamide, a triad sold under the brand name Biktarvy in the U.S, according to an afternoon presentation by Anne F. Luetkemeyer, M.D., a professor of medicine at the University of California, San Francisco, and an attending physician at San Francisco General Hospital where she specializes in HIV/AIDS.

The primary end point was a commonly used measure of viral load, an HIV-1 RNA level of 50 copies per milliliter (mL) or more. Data shared by Luetkemeyer showed that after 24 weeks of treatment, none of the 78 study participants randomly selected to switch from treatment with Biktarvy had crossed the HIV-1 RNA level of 50 copies per mL threshold, while one of the 79 study participants who continued on Biktarvy did.

Because of the islatravir’s backstory as an agent that caused CD4+ T cells to drop to possibly harmful levels, the data that Luetmeyer showed on the CD4+ T cell counts might strike some as just as, if not more, important as the viral load results. The abstract of the findings that Luetmeyer presented showed that study participants who switched to islatravir-ulonivirine experienced a slight increase in CD4+ T cells (6.9 cells per mL starting at a baseline of 833, on average) as measured at week 24 while those that continued with Biktarvy experienced a slight decrease (-13.6 cells per mL starting at a baseline of 898, on average).

The data that Luetmeyer presented showed that the adverse event rates were similar between the islatravir-ulonivirine group (45 out of 78 had one adverse event or more) and the Biktarvy group (44 out of 79) but the treatment-related adverse events were far more common in the study participants who switched to islatravir-ulonivirine (10 of 78, or approximately 13%, compared with none among those who continued with Biktarvy. As the investigator who presented the open-label trial results for islatravir-lenacapavir trial noted, it is a common pattern to see spikes in treatment-related adverse events in open-label switching studies. Other than the treatment-related adverse events, the side effect and safety data from the trial didn’t signal safety issues with islatravir-ulonivirine. Three serious adverse events occurred in the islatravir-ulonivirine group, but none were considered drug-related. One study participant discontinued treatment after a grade 2 skin reaction.

"The combination of islatravir 2 mg given with ulonivirine 200 mg as an oral once-weekly antiretroviral option maintained viral suppression through week 24 with efficacy comparable to continuing daily [Biktarvy]," Luetkemeyer said during the presentation, adding that the switch “was generally well tolerated” with no new safety concerns identified. Because of the positive finding, Merck is going ahead with phase 3 trials to once-weekly islatravir-ulonivirine.

During the question-and-answer period, Luetkemeyer spoke about the advantages of pursuing development of another weekly treatment pill for HIV even if the research results for islatravir-lenacapavir are leaning in such a positive direction. He said mention that the two pairings may have different resistance profiles and that the competition might increase access. “I think more is better,” said Luetmeyer. “I’m glad to see drug development occurring because I think our patients are the one who are going to benefit.”

Ulonivirine is a non-nucleoside reverse transcriptase inhibitor with activity against HIV strains that have developed resistance to older drugs. Attacking HIV on multiple fronts has been shown to be the best way to contain the virus, so ulonivirine’s developer, Merck, has been investigating various pairings, including with Islatravir.