A once-daily combination pill containing bictegravir and lenacapavir could offer a simpler alternative for people with HIV who are taking complex antiretroviral regimens, according to study results presented yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) in Denver.
Gilead Sciences is testing a new single-tablet regimen consisting of 75mg bictegravir and 50mg lenacapavir (BIC/LEN). Bictegravir is an oral integrase inhibitor best known as a component of the widely used Biktarvy combination pill (bictegravir/tenofovir alafenamide/emtricitabine). Lenacapavir is the first HIV capsid inhibitor. A twice-yearly injectable formulation is currently approved as a component of combination treatment for multidrug-resistant HIV (Sunlenca) and for pre-exposure prophylaxis (Yeztugo, Yeytuo). It is also available as a pill used as an initial loading dose before starting injections.
“Most people in the world living with HIV are taking single-tablet regimens, however, there are still many people who have to take complex, multi-tablet regimens, often due to viral resistance, intolerance or contraindications,” said presenter Professor Chloe Orkin of Queen Mary University of London.
“In many cases, these individuals are our elders, diagnosed early in the pandemic. They may experience a high pill burden and challenges with adherence and may be at risk for drug interactions due to the boosted protease inhibitors they’re taking,” she continued. “So this is a clear unmet need, and a novel drug such as BIC/LEN could optimise treatment for individuals with viral suppression who are on these complex regimens.”
ARTISTRY-1
Orkin presented findings from the open-label ARTISTRY-1 trial (NCT05502341), which evaluated bictegravir plus lenacapavir as a switch option for people taking complex regimens. The phase II portion of the study tested bictegravir and lenacapavir as separate pills, while the phase III portion used the new single-tablet regimen.
At the 2024 International AIDS Conference, researchers reported results from the phase II portion, showing that about 90% of people with viral suppression who switched to bictegravir plus one of two doses of lenacapavir taken as separate pills had a viral load below 50 copies at 48 weeks, as did everyone who stayed on their existing regimen; these results held at 96 weeks.
Late last year, Gilead announced top-line results from the phase III portion, showing that the BIC/LEN combination pill worked as well as continuing on complex regimens. Orkin presented the details at CROI, and they were published simultaneously in The Lancet.
The phase III portion enrolled 557 adults in 15 countries who were on stable complex multi-tablet regimens. They were randomly assigned in a 2:1 ratio to switch to BIC/LEN or stay on their existing regimen.
The study population was older than that of most HIV trials; the median age was 60 years and three-quarters were older than 55. About one in five were women. Most (69%) were White, 17% were Black, 5% were Asian and 22% were Latino. Co-morbidities were common, including elevated blood lipids (68%), high blood pressure (50%), high blood sugar or diabetes (24%) and chronic kidney disease (14%). More than half had two or more co-morbidities and 61% were taking two or more medications besides antiretrovirals. The current median CD4 cell count exceeded 600, but two-thirds had a history of AIDS.
At study entry, the participants had been on antiretroviral therapy for a median of 28 years longer than some of the younger investigators had been alive, Orkin noted. Complex regimens were defined as those that included two or more pills per day, required more than once-daily dosing or contained a boosted protease inhibitor, an NNRTI plus two other drug classes or injected medication besides cabotegravir and rilpivirine (Vocabria and Rekambys).
Three-quarters were taking boosted protease inhibitors and a majority used both a protease inhibitor and an integrase inhibitor. Most were taking two (41%) or three (26%) pills per day, but 22% were taking five or more; 39% took their pills twice daily. The most common reason for using a complex regimen was drug resistance (81%), followed by intolerance (23%) or contraindications (6%) to single-tablet regimens. Many had a history of resistance to NRTIs (67%), NNRTIs (55%) or protease inhibitors (41%), but integrase inhibitor resistance was rare (5%).
BIC/LEN was shown to be noninferior to staying on a complex regimen, Orkin reported. At 48 weeks, 96.0% of those on the single-tablet regimen had an undetectable viral load, compared with 93.5% of those who stayed on their existing regimen. 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 groups.
BIC/LEN was generally safe and well tolerated. While overall adverse event rates were similar in both groups, people assigned to BIC/LEN were more likely to experience drug-related events (14.3% versus 1.6%) – not surprising, as side effects typically occur when people start new medications. Two people taking BIC/LEN had grade 3 or higher drug-related adverse events, and one had a serious side effect (diabetes). There were five deaths in the BIC/LEN group, all considered unrelated to treatment.
Six people on BIC/LEN and one person on a complex regimen discontinued treatment due to adverse events, including one who showed evidence of hepatitis B reactivation. This is a potential risk when people stop taking drugs, such as tenofovir, that are active against both HIV and hepatitis B virus. This underscores the importance of hepatitis B vaccination for those who are not already immune.
The study also looked at changes in blood lipids. People taking BIC/LEN saw decreases in cholesterol and triglycerides – largely attributable to stopping a protease inhibitor – while those on complex regimens had a small increase. Orkin said that a detailed analysis of cardio-metabolic outcomes, including weight changes, is underway.
Turning to patient-reported outcomes, people in both groups had similar satisfaction scores, but those who switched from a complex regimen to BIC/LEN reported increased satisfaction with their treatment.
“These data suggest that the BIC/LEN single-tablet regimen is an important option enabling treatment to be tailored for people with virological suppression on a complex regimen,” the researchers concluded.
In a discussion of conference highlights, Dr Paul Sax of Brigham and Women’s Hospital wondered why people are still taking complex regimens, suggesting that most could maintain viral suppression if they switched to Biktarvy, without concerns about hepatitis B reactivation. Dr Joseph Eron of the University of North Carolina at Chapel Hill concurred: “They could have done the same study of Biktarvy versus complex regimens and it would have shown the same thing.”
Nonetheless, if BIC/LEN is approved, people on complex regimens could soon have a new option to simplify therapy and improve treatment satisfaction.
ARTISTRY-2
Researchers also presented results from the ARTISTRY-2 trial (NCT06333808) in a poster at the conference. This study evaluated the BIC/LEN single-tablet regimen as a switch option for people currently taking Biktarvy.
In this trial, 574 people with viral suppression on Biktarvy were randomly assigned in a 2:1 ratio to either switch to BIC/LEN or stay on their current treatment. Unlike the open-label ARTISTRY-1 study, this trial was double-blind, meaning neither the participants nor the investigators knew who was assigned to which regimen.
This study population was younger, with a median age of 49 years and about a third being age 55 or older. Again, nearly 20% were women, but participants were more racially diverse (54% White, 27% Black, 13% Asian and 27% Latino). The population was generally healthier, but co-morbidities were still common, including elevated blood lipids (41%), high blood pressure (36%), high blood sugar or diabetes (17%) and chronic kidney disease (6%).
Here, too, the new single-tablet regimen was shown to be non-inferior. At 48 weeks, 93.5% of people assigned to BIC/LEN had an undetectable viral load, as did 90.6% of those who stayed on Biktarvy. Five people (1.3%) in the BIC/LEN group and two (1.0%) in the Biktarvy group had a viral load above 50 copies. One person in the BIC/LEN group, who had previously taken integrase inhibitors, had an integrase resistance mutation. Again, CD4 counts remained stable in both groups.
Both regimens were safe and generally well tolerated. The likelihood of drug-related adverse events was similar in the BIC/LEN and Biktarvy groups (10.4% and 12.0%). Only one person in the BIC/LEN group had a grade 3 or higher side effect (rhabdomyalysis, or muscle damage). Six people in the BIC/LEN group and three in the Biktarvy group discontinued treatment due to adverse events. Weight and body mass index stayed about the same in both groups.
“These 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,” the researchers concluded.
“The findings from ARTISTRY-2 support the potential of the bictegravir/lenacapavir regimen to expand the range of single-tablet antiretroviral treatments available to people living with HIV,” lead investigator Dr Eric Meissner of the Medical University of South Carolina said in a Gilead news release. “With efficacy shown to be comparable to a guideline-recommended therapy, we look forward to the prospect of having another meaningful treatment option for adults with HIV who are virologically suppressed.”
Gilead indicated that it plans to submit the ARTISTRY-1 and ARTISTRY-2 study results to regulatory authorities for consideration of approval.
