New Once-Daily HIV Oral Alternative Advances

A once-daily oral combination therapy for HIV — bictegravir plus lenacapavir — is more effective than complex regimens are, according to results from a phase 2 study of people with HIV who are virologically suppressed, presented the Conference on Retrovirus and Opportunistic Infections (CROI) in Denver.

The multicenter ARTISTRY-1 trial, sponsored by Gilead Sciences, compares the investigational once-daily pill — a combination of bictegravir, an integrase strand transfer inhibitor, and lenacapavir, a first-in-class capsid inhibitor — with current complex regimens.

Single-table regimens have been available for more than a decade, but an estimated 8% of people with HIV cannot take them and instead must take a complex treatment regimen, defined as two or more pills each day. And some study participants were on regimens that combined pills and infused drugs.

Trouble With Existing Options

There are many reasons people living with HIV haven’t been able to start any of the 11 currently available single-tablet options, including drug resistance, intolerance, toxicity, drug-drug interactions, and contraindications, said Antonio E. Urbina, MD, medical director of the downtown clinic for the Mount Sinai Institute for Advanced Medicine and professor of medicine in infectious diseases at the Icahn School of Medicine in New York City. 

“This combination of bictegravir and lenacapavir is highly anticipated as it offers the potential for a single tablet for this population, optimizing their treatment and reducing pill burden,” said Urbina, who was not part of the study. 

The study involved 128 participants who had been on a stable baseline regimen for at least 6 months before screening. They were randomly assigned in a 2:2:1 ratio to a low-dose once-daily oral regimen that consisted of bictegravir 75 mg + lenacapavir 25 mg (n= 51); a high-dose regimen that consisted of bictegravir 75 mg + lenacapavir 50 mg (n= 52); or a continuation of their current complex regimen (n= 25). 

The primary endpoint was the proportion of patients without virologic suppression (an HIV viral load ≥ 50 copies/mL) at week 24. Key secondary endpoints included the number of participants with virologic suppressions (an HIV viral load < 50 copies/mL) and the number of participants with treatment-emergent adverse events. 

Good Virologic Suppression

All three groups had good virologic suppression at 6 months, with consistently low viral loads throughout the study, the data show. None of the participants in the low-dose group or in the complex-regimen group had experienced a viral load rebound (≥ 50 copies/mL) at week 24. In the high-dose group, only one participant experienced a viral load increase above the threshold, but that was suppressed without a change in regimen. 

In addition, both bictegravir-lenacapavirregimens showed favorable safety profiles. Up to week 24, the most common side effects in the low-dose and high-dose groups were diarrhea (7%), COVID-19 (6%), and constipation (5%). Drug-related adverse events leading to discontinuation were reported in 2% of participants in the high-dose group, 2% in the low-dose group, and 0% in the complex-regimen group. 

Most Side Effects Mild

“Most treatment-emergent adverse events were grade 1 or 2, and the incidence of grade 3 or higher events were low and comparable across the treatment groups. The majority of grade 3/4 laboratory abnormalities were either consistent with a participant’s medical history or transient and not clinically significant,” Urbina points out. 

However, he cautioned, this is a small number of patients and a 24-week follow-up; longer-term safety data will be needed to fully assess safety. 

“It is common to see a higher rate of adverse events reported in the switch arm of a study,” explained Elizabeth Sherman, Pharm D, associate professor of pharmacy practice at Nova Southeastern University in Fort Lauderdale, Florida, an d an HIV/AIDS clinical pharmacy specialist, who was also not part of the study. 

“When you take a population of people who are stable on antiretroviral therapy and randomize them to new medications, adverse events are frequently reported. This happens more often than the occurrence of new adverse events in the population of people randomized to remain on their same ART regimen,” she added. 

One of the most promising aspects of this study, Sherman said, is that most participants were on a boosted protease inhibitor at baseline and were able to remove the booster from their regimen because of the switch to the combination. 

“This instantly mitigates several drug interactions and removes the food requirement, streamlining the patients’ therapy while reducing pill burden,” she added. 

Participants had long histories on multiple-drug regimens and were on antiretroviral therapy for a median 27 years. “It’s remarkable that individuals with such a long treatment history could now be eligible for a single-tablet regimen,” she said. 

Unanswered Questions

Other information would be good to have, such as the known antiretroviral resistance mutations of the participants at baseline, the experts report. Further research will also help answer how long people on the new option will be able to maintain viral suppression. 

Additional questions include the use of the single tablet for people on multiple-tablet regimens without virologic suppression at baseline and the use of this regimen for untreated patients, Sherman explained. 

“Also, we can’t forget about people with hepatitis B coinfection,” she added. “It seems that all single tablet regimens and long-acting agents in later stages of development do not meet the needs of individuals with HIV-HBV co-infection.” 

Urbina said that he would like to see, in further studies, quality-of-life and patient-reported outcomes data, pharmacokinetic data, and potential drug-drug interactions because this combination might be used with concomitant medications. 

Although both combination doses were effective, the phase 3 trial is using the higher dose (bictegravir 75 mg + lenacapavir 50 mg) because it has better “forgiveness,” covering patients if they happen to miss a dose, said principal investigator and presenting author Karam Mounzer, MD, who is chief scientific officer at Philadelphia FIGHT in Pennsylvania.

The phase 3 48-week study is expected to conclude by the end of 2025, with analysis in early 2026, he reported.

The rationale for these trials “is to simplify patients’ lives,” Mounzer explained. “Simplicity, when it comes to HIV treatment, equals adherence.” 

Marcia Frellick, a graduate of Northwestern University’s Medill School of Journalism, has been a Chicago-based healthcare journalist for more than 20 years. Her move to writing followed a progression of editing roles at the St. Cloud Times, the Iowa City Press-Citizen, the Cincinnati Enquirer, and the Chicago Sun-Times. Her writing has appeared in the Chicago Tribune, Science News, and Northwestern Magazine in addition to Medscape Medical News, MDEdge, and WebMD.