DOR/ISL noninferior to comparator ARTs in two phase III trials

In adults with virologically suppressed HIV-1* infection, switching to a two-drug regimen of doravirine 100 mg and islatravir 0.25 mg (DOR/ISL) was noninferior to continuing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) or other baseline antiretroviral therapy (bART) regimens in maintaining viral suppression at 48 weeks, according to two phase III trials presented at CROI 2025.

“There remains an unmet need for novel ART regimens that have high potency while maintaining viral control and pose a low risk of long-term toxicity,” said Dr Amy Colson from the Community Resource Initiative in Boston and Cambridge Health Alliance in Cambridge, Massachusetts, US, who presented the MK-8591A-052 study.

“Despite the availability of multiple daily ARTs, the needs of people living with HIV are evolving. Many people living with HIV are older and managing comorbidities, making it important to have daily treatment options that can help meet their unique health needs,” said Professor Chloe Orkin from Queen Mary University of London, UK, who presented the MK-8591A-051 study, in a press release.

“I’m excited to see that DOR/ISL has the potential as a new daily treatment option for people living with HIV who may benefit from this two-drug regimen,” she noted.

MK-8591A-052

This ongoing phase III, double-blind trial involved 513 adults (median age 47 years, 21.4 percent female) with HIV-1 who were virologically suppressed for ≥3 months on BIC/FTC/TAF, with no history of treatment failure or known resistance to DOR. Participants were randomized in a 2:1 ratio to switch to DOR/ISL (n=342) or to continue BIC/FTC/TAF (n=171). [CROI 2025, abstract 204A]

At week 48, five participants had met the primary endpoint of HIV-1 RNA ≥50 copies/mL in the DOR/ISL arm compared with one participant in the BIC/FTC/TAF arm (1.5 percent vs 0.6 percent; treatment difference, 0.9 percent, 95 percent confidence interval [CI], -1.9 to 2.9), which was within “the prespecified noninferiority margin of 4 percent, demonstrating that switching to DOR/ISL was noninferior to continuing BIC/FTC/TAF,” said Colson.

In addition, the rate of viral suppression (HIV-1 RNA <50 copies/mL) was similarly high and maintained at week 48 in both arms, with 91.5 percent of those who switched to DOR/ISL compared with 94.2 percent of those who continued on BIC/FTC/TAF (treatment difference, -2.6 percent, 95 percent CI, -7.1 to 2.6).

“This is the first phase III trial to demonstrate that a two-drug regimen, without an integrase inhibitor, was noninferior to BIC/FTC/TAF,” Colson highlighted.

MK-8591A-051

This ongoing phase III, open-label trial included 551 adults (median age 51 years, 39.7 percent female) with HIV-1 who were virologically suppressed for ≥3 months on stable, oral two- or three-drug ART, and had no evidence of virologic failure or known resistance to DOR. Participants were randomized in a 2:1 ratio to switch to DOR/ISL (n=366) or to continue bART (n=185). [CROI 2025, abstract 204B]

By week 48, only five individuals who switched to DOR/ISL had a viral load of ≥50 copies/mL compared with nine of those who continued bART (1.4 percent vs 4.9 percent; treatment difference, -3.6 percent, 95 percent CI, -7.8 to -0.8). “This falls below the 4 percent noninferiority margin, demonstrating the noninferiority of DOR/ISL to bART,” Orkin noted.

Moreover, 95.6 percent of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) at week 48 compared with 91.9 percent of those who continued on bART (treatment difference, 3.7 percent, 95 percent CI, -0.3 to 8.9).

Safety parameters

“Prior phase III studies of DOR/ISL, using a daily ISL dose of 0.75 mg showed declines in the CD4 count and the absolute lymphocyte count,” said Colson. “A phase IIb dose-finding study suggests that such declines would not be expected with the lower 0.25-mg daily ISL dose used in this study.”

In both the MK-8591A-052 and MK-8591A-051 trials, the mean percent change in CD4 T-cell count and total lymphocyte count from baseline to week 48 was similar in both treatment groups.

Only 0.6 percent of participants in each group discontinued treatment due to decreased CD4 T-cell or total lymphocyte count in the MK-8591A-052 study (DOR/ISL and BIC/FTC/TAF), while none was observed in the MK-8591A-051 study (DOR/ISL and bART).

“DOR/ISL may provide an efficacious non-InSTI** switch option for people living with HIV-1. This supports the development of longer-acting ISL-based therapies,” Orkin added.