By Liz Highleyman
All modern antiretroviral therapy is highly effective, so choosing a regimen often comes down to ease of use. In late August, the Food and Drug Administration approved Gilead Sciences’ Bixlenvo (bictegravir/lenacapavir), a new once-daily single-tablet regimen that could be an attractive switch option for people currently taking more complex regimens.
But treatment that can be taken less often is the real game-changer. Some people have trouble taking a daily pill, which reminds them of having HIV every day. While long-acting injectables are the answer for some, others find it inconvenient to schedule injection appointments, or they simply don’t want shots.
Fortunately, two weekly combination pills are on the horizon. As reported at this summer’s International AIDS Conference (AIDS 2026) in Rio de Janeiro, a once-a-week tablet containing islatravir and lenacapavir was shown to be safe and effective in two late-stage clinical trials. Further back in the pipeline, a weekly one-pill regimen containing islatravir and ulonivirine also looks promising.
“Treatment needs to fit into people’s lives, not the other way around,” International AIDS Society president Kenneth Ngure, PhD, MPH, said in a news release. “People living with HIV need new treatment options that offer flexibility, and a weekly pill could broaden the choices available for adults with virological suppression.”
Two Phase 3 studies evaluated the weekly islatravir/lenacapavir combination pill as a switch option for people with viral suppression on daily oral treatment, after an earlier Phase 2 trial showed that islatravir plus lenacapavir taken as separate pills once a week maintained an undetectable viral load.
Islatravir, from Merck, is the first nucleoside reverse transcriptase translocation inhibitor, which works a bit differently than the familiar nucleoside/nucleotide reverse transcriptase inhibitors in most current regimens. Development of islatravir hit a snag in late 2021 when some people in early treatment and PrEP trials saw a decline in their CD4 T-cell or total lymphocyte counts. But scientists determined that the doses studied were too high, and the FDA allowed trials to resume using lower doses that do not cause this side effect. A once-daily pill containing islatravir and Merck’s NNRTI doravirine, sold as Idvynso, was approved in April.
Gilead’s lenacapavir is the first HIV capsid inhibitor. A twice-yearly injectable formulation is already approved as a component of combination treatment for multidrug-resistant HIV (brand name Sunlenca) and as a solo drug for PrEP (Yeztugo). But these studies used an oral formulation like the one in the new Bixlenvo combo pill.
ISLEND-1 (NCT06630286) enrolled 607 people in the United States and 10 other countries. The median age was approximately 49 years, and 17% were older than 65, reflecting the aging HIV population. Nearly 80% were men, and the population was racially and ethnically diverse. At study entry, they were taking Gilead’s Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) and had a viral load below 50 for at least six months.
ISLEND-2 (NCT06630299) enrolled 626 people in 13 countries. Population demographics were generally similar. At study entry, they had viral suppression on various standard-of-care daily oral combinations. Most were taking a single-tablet regimen, and 76% were on a combination that included an integrase inhibitor.
The participants in both studies had no history of virological treatment failure. They also did not have hepatitis B and most had evidence of hepatitis B virus (HBV) immunity due to prior infection or vaccination. This is important because neither islatravir nor lenacapavir is active against HBV, unlike tenofovir and some other commonly used HIV medications.
In both trials, participants were randomized to either stay on their existing regimen or switch to a once-weekly combination pill containing 2 mg islatravir and 300 mg lenacapavir. ISLEND-1 was double-blind, meaning neither the researchers nor the participants knew who was assigned to which group, while ISLEND-2 was open-label, meaning everyone knew who got what.
In June, Merck and Gilead announced positive topline findings from the studies, showing that the islatravir/lenacapavir combo pill was non-inferior to staying on current treatment, meaning it worked at least as well. Detailed results were presented at AIDS 2026.
In ISLEND-1, 93.4% of people who switched to the weekly islatravir/lenacapavir pill and 92.4% of those who stayed on daily Biktarvy maintained viral suppression at 48 weeks. No one on the combination pill and one person on Biktarvy had a viral load of 50 or higher. No emergent resistance to islatravir or lenacapavir was detected.
In ISLEND-2, 95.2% of people who switched to the new weekly coformulation and 95.5% of those who stayed on their existing daily regimen maintained viral suppression. One person who switched to islatravir/lenacapavir and four people who did not change their treatment had a viral load of 50 or higher. Again, no emergent resistance was detected.
In both trials, the weekly islatravir/lenacapavir pill was generally well tolerated, and adherence was very high. The most frequently reported adverse effects were nausea, headache and diarrhea. Side effects were mostly mild to moderate, and few people stopped treatment for this reason. One unvaccinated person discontinued treatment after testing positive for hepatitis B. Body weight did not change. And importantly, people taking the new combo pill did not experience white blood cell decreases like those seen with higher doses of islatravir.
ISLEND-2 also looked at patient-reported outcomes. Among those who switched, more than 75% said they were more satisfied with the weekly pill, 14% were equally satisfied and about 3% preferred their prior daily treatment.
Annie Luetkemeyer, MD, of the University of California San Francisco presented findings from a study of another weekly oral combination at an earlier stage of development.
This Phase 2 trial (NCT06891066) evaluated 2 mg islatravir plus 200 mg ulonivirine taken as separate pills once a week. Ulonivirine is a next-generation NNRTI from Merck that remains active against HIV that has developed resistance to older drugs in its class.
This open-label trial enrolled 157 people in the United States, Australia and Switzerland. The median age was 48 years, nearly three quarters were men, and they were racially and ethnically diverse. At study entry, they were on once-daily Biktarvy with a viral load below 50 for at least six months. They had no history of treatment failure and no known ulonivirine resistance. People with active hepatitis B or C were excluded, but about a quarter lacked evidence of HBV immunity.
The study participants were randomly assigned to switch to once-weekly islatravir plus ulonivirine—a regimen consisting of four pills—or remain on their current daily regimen. At 24 weeks, 94.9% of people who switched and 97.5% of those who stayed on Biktarvy maintained viral suppression. No one on the experimental regimen and one person on Biktarvy had a viral load of 50 or higher. However, none had a viral load of 200 or higher and met the criteria for drug resistance testing.
Here, too, treatment was safe and generally well tolerated. Ten people on islatravir plus ulonivirine and none who stayed on Biktarvy experienced drug-related adverse events. Luetkemeyer noted that this difference is not unusual in open-label switch studies, as side effects usually emerge soon after starting a new medication. No one in either group had severe adverse events. Body weight changes were minor, and no one experienced hepatitis B reactivation. Changes in CD4 and total lymphocyte counts were comparable in both groups, again confirming the safety of the 2 mg islatravir dose.
Given these promising findings, this comparison will continue through 48 weeks, at which point those initially assigned to Biktarvy will switch to islatravir plus ulonivirine. At 96 weeks, participants will start taking a new islatravir/ulonivirine combination pill. This weekly coformulation will also be evaluated as a switch option in the forthcoming Phase 3 SYMPHORIA trials.
Gilead is preparing to submit its Phase 3 findings to the FDA, suggesting that the islatravir/lenacapavir combination pill could be approved as a switch option next year, making it the first oral regimen that does not require daily pills.
“The once weekly oral islatravir/lenacapavir HIV regimen will be an exciting option for our patients who struggle with adherence to a daily pill,” San Francisco AIDS Foundation medical director Hyman Scott, MD, MPH, told BETA. “The current long-acting HIV treatment options have been a game-changer for many of our patients, but all require injections. Being able to offer this long-acting oral option for people who cannot tolerate injections will be just as transformative and will hopefully foster newer regimens that require even less frequent dosing (such as monthly).”
If the experimental islatravir/ulonivirine coformulation proves its mettle in Phase 3, a second once-weekly oral option might come online in late 2028 or 2029. If both weekly combo pills are approved, competition could lower cost and improve access. In the usual progression, drugs that are initially approved as a switch option for treatment-experienced people may later become available as first-line therapy for previously untreated people.