A new once-daily pill could simplify treatment for people with drug resistance

Globally, at least 10% of adults with HIV—and up to 20% of highly treatment- experienced adults—have developed resistance to common antiretroviral drugs, according to the World Health Organization. 

This subset of people with HIV (PWH) was the focus of research on a new once-daily drug combination of bictegravir + lenacapavir (BIC/LEN) presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in February. Results from two studies, presenters said, promise relief from the struggle with drug resistance and complex, multi-tablet regimens, even for older, heavily treatment-experienced PWH. 

Presenting results from the open-label ARTISTRY-1 trial, Chloe Orkin, MBBCH, MSc, a professor at Queen Mary University of London, said that the target population for this research is virally suppressed people who may have been diagnosed with HIV decades ago, and who have a high pill burden and risk drug interactions. “This is a clear unmet need, and a novel drug such as BIC/LEN could optimize treatment for individuals with viral suppression who are on these complex regimens,” she said.

The single-tablet regimen of BIC/LEN being tested by Gilead Sciences consists of 75 mg of bictegravir, an oral integrase inhibitor used in the Biktarvy combination pill (bictegravir/tenofovir alafenamide/emtricitabine), plus 50 mg of lenacapavir, the first of its class HIV capsid inhibitor. A twice-yearly injectable formulation of lenacapavir is already approved as a component of combination treatment for multidrug-resistant HIV (brand name Sunlenca) and for PrEP (Yeztugo). 

In sharing top line results of phase 3 of ARTISTRY-1, which were simultaneously published in The Lancet, Dr. Orkin emphasized that the study population was older than that of most HIV trials, with a median age of 60 years—three-quarters of participants were older than age 55. 

Results from phase 2 of ARTISTRY-1, which evaluated bictegravir and lenacapavir as separate pills, were presented at the 2024 International AIDS Conference, and showed that 90% of people with viral suppression who switched to bictegravir + lenacapavir, taken as separate pills, had a viral load below 50 copies at 48 weeks, similar to participants who remained on their current regimen.

Phase 3 of ARTISTRY-1, which tested BIC/LEN as a single tablet, concluded that the BIC/LEN combination was just as effective as Biktarvy with no treatment-emergent resistance observed in most cases.

Digging into the phase 3 details, 20% of participants were women, 69% were white, 22% Latino, 17% Black and 5% were Asian. Co-existing conditions included elevated blood lipids (68%), high blood pressure (50%), high blood sugar or diabetes (24%) and chronic kidney disease (14%), with more than half experiencing at least two comorbidities. The pill burden was high: nearly two-thirds of participants were on two or more meds in addition to ART. Median CD4 cell count was greater than 600. Two-thirds had a history of AIDS.

Participants had been on antiretroviral therapy for a median of 28 years, and most were on complex HIV regimens, including 41% taking two pills a day, 26% taking three pills a day and 22% taking five or more daily. Three-quarters were on boosted protease inhibitors and most used a protease inhibitor along with an integrase inhibitor. 

The vast majority were taking complex regimens due to drug resistance (81%). Others took multiple pills due to drug intolerance (23%) or contraindications (6%) to single-tablet regimens. There was a large amount of resistance to the HIV drugs nucleoside reverse transcriptase inhibitors (NRTIs; 67%), non-nucleoside reverse transcriptase inhibitors (NNRTIs; 55%) or protease inhibitors (41%). However, only 5% had resistance to integrase inhibitors (INSTIs). 

“There was significant historical resistance among all of these regimens,” Dr. Orkin said. 

At 48 weeks, 96.0% of participants on single-tablet BIC/LEN had an undetectable viral load, compared with 93.5% of those remaining on their regimens. 

Three people (0.8%) in the BIC/LEN group and two (1.1%) in the complex-regimen group had a viral load above 50 copies. No treatment-emergent resistance to the study drugs was observed. CD4 counts remained stable in both arms over the 48 weeks of treatment.

BIC/LEN was generally safe and well tolerated. The rate of adverse events was similar in both groups, however people assigned to BIC/LEN were more likely to experience drug-related events (14.3% versus 1.6%). This was to be expected, as side effects are more common in people starting new medications, Orkin said. Two people taking BIC/LEN had grade 3 or higher drug-related adverse events, predominantly upper respiratory related or headache. In all, only six people in the BIC/LEN group, and one on the complex regimen, discontinued treatment due to adverse events. There were five deaths in the BIC/LEN group, but these were considered unrelated to treatment.

Especially important for this group, there were no treatment-emergent resistant mutations in the group taking BIC/LEN. While there have been rare cases of resistance to LEN in other trials, data from ARTISTRY studies suggest a high barrier to resistance for this combination. Even when resistance does occur with LEN, it often leads to a “less fit” virus with significant replication defects, making it harder for the virus to survive.

Dr. Orkin shared good news for people with high cholesterol and triglycerides: participants on BIC/LEN saw decreases in LDL, triglycerides and total cholesterol, likely due to stopping their protease inhibitors, although HDL (“good cholesterol”) was unchanged. She said that research on other metabolic changes is ongoing. 

People in both groups had similar satisfaction scores, but participants who switched from a complex regimen to BIC/LEN reported increased satisfaction with the new treatment.

“These data suggest that the BIC/LEN single-tablet regimen is an important option, enabling treatment to be tailored for people with viral suppression on complex regimens,” Dr. Orkin concluded. 

BIC/LEN just as effective as Biktarvy in younger people with HIV

In a poster session at CROI 2026, researchers shared results from the ARTISTRY-2 trial, which evaluated the BIC/LEN single-tablet regimen as a potential option for people currently on Biktarvy. 

Researchers randomly assigned 574 virally suppressed people with HIV, all taking Biktarvy, to either switch to BIC/LEN or stay on their current treatment. There were several differences between the two ARTISTRY trials: Unlike ARTISTRY-1, ARTISTRY-2 was double-blind—neither the research team nor the study participants knew who was getting what. The study population was younger in ARTISTRY-2, with a median age of 49 years and one-third being age 55 or older. Similar to ARTISTRY-1, 20% were women, but ARTISTRY-2 had more racial diversity (54% white, 27% Black, 27% Latino and 13% Asian). And while the population of ARTISTRY-1 was generally healthier, participants still had health issues, including elevated blood lipids (41%), high blood pressure (36%), high blood sugar or diabetes (17%) and chronic kidney disease (6%).

As with ARTISTRY-1, the single BIC/LEN tablet was found to be non-inferior to participants’ current regimens. At 48 weeks, 93.5% of people in the BIC/LEN arm had an undetectable viral load, versus 90.6% for those remaining on Biktarvy, and CD4 counts remained stable in both groups. Only five people (1.3%) in the BIC/LEN group and two (1.0%) in the Biktarvy group had a viral load above 50 copies per mL. One person in the BIC/LEN arm, who had previously taken integrase inhibitors, was found to have an integrase resistance mutation. 

BIC/LEN was found safe and generally well tolerated, with the likelihood of drug-related adverse events similar in both Biktarvy and BIC/LEN arms (10.4% and 12.0%, respectively). Six people in the BIC/LEN group and three in the Biktarvy group discontinued treatment due to adverse events. 

Researchers concluded that the results are “consistent with those of ARTISTRY-1 and support the use of a novel BIC/LEN single-tablet regimen to expand treatment options for people with HIV with virologic suppression [undetectable viral load].”

On NPR’s All Things Considered, Linda-Gail Bekker, MBChB, DTMH, DCH, FCP (SA), director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, said that both ARTISTRY-1 and ARTISTRY-2, as well as similar research, are crucial for staying ahead of HIV’s tendency to mutate and develop resistance.

The drugmaker, Gilead Sciences, says it will use ARTISTRY-1 and ARTISTRY-2 results to file for FDA approval this year, with a possible rollout of BIC/LEN in the second half of 2026.