Merck's Doravirine/Islatravir Combination Demonstrates Non-Inferiority in Phase 3 HIV Treatment Trials
Key Insights
Merck (search)'s investigational two-drug regimen doravirine/islatravir (DOR/ISL) achieved non-inferiority to standard three-drug therapy in treatment-naïve HIV-1 (search) patients, with 91.8% achieving viral suppression at 48 weeks.
The combination represents the first non-INSTI two-drug regimen to demonstrate comparable efficacy and safety to bictegravir/emtricitabine/tenofovir alafenamide in previously untreated adults with HIV-1 (search).
Extended 96-week data showed DOR/ISL maintained high viral suppression rates in patients who switched from other antiretroviral therapies, supporting its potential as a treatment simplification option.
Merck (search) announced compelling results from three pivotal Phase 3 trials evaluating its investigational once-daily, two-drug HIV treatment regimen doravirine/islatravir (DOR/ISL) at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. The findings represent a significant advancement in HIV treatment simplification, demonstrating that a non-integrase strand transfer inhibitor (search) (INSTI) two-drug combination can match the efficacy of current three-drug standard-of-care regimens.
Treatment-Naïve Population Shows Strong Efficacy
The Phase 3 MK-8591A-053 trial evaluated DOR/ISL (100 mg/0.25 mg) versus bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in 536 adults with HIV-1 (search) who had not previously received antiretroviral treatment. The study met its primary efficacy endpoint, demonstrating non-inferiority at Week 48 with 91.8% of DOR/ISL patients achieving viral suppression (HIV-1 RNA <50 copies/mL) compared to 90.6% on BIC/FTC/TAF (treatment difference 1.2%, 95% CI: -3.7, 6.2, p<0.001).
"These new Phase 3 results are meaningful, showing that an investigational two-drug regimen without an INSTI demonstrated non-inferior efficacy and a comparable safety profile versus BIC/FTC/TAF in previously untreated adults with HIV-1 (search), including those with advanced disease," said Dr. Jürgen K. Rockstroh, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn.
The trial included a challenging patient population, with 36.8% having baseline HIV-1 (search) RNA >100,000 copies/mL, 10.3% with >500,000 copies/mL, and 17.2% with CD4+ T-cell counts <200 cells/mm³. Notably, DOR/ISL showed superior efficacy in high viral load subgroups, achieving 94.0% vs 87.6% viral suppression in patients with screening HIV-1 RNA >100,000 copies/mL, and 90.3% vs 84.4% in those with >500,000 copies/mL.
Favorable Safety Profile Maintained
Safety outcomes were comparable between treatment groups, with drug-related adverse events reported in 14.1% of DOR/ISL patients versus 18.0% on BIC/FTC/TAF. Discontinuation rates due to adverse events were similarly low at 1.1% for DOR/ISL and 2.2% for BIC/FTC/TAF. Immune reconstitution parameters showed no significant differences between groups, with similar increases in CD4+ T-cell counts and total lymphocyte counts.
Switch Studies Demonstrate Sustained Efficacy
Two additional Phase 3 trials evaluated treatment switches to DOR/ISL in virologically suppressed patients. The MK-8591A-052 study involved 513 adults switching from BIC/FTC/TAF to DOR/ISL, while MK-8591A-051 included 551 patients switching from various baseline antiretroviral therapies (bART).
At 96 weeks, both switch studies maintained high rates of viral suppression. In the BIC/FTC/TAF switch study, 88.9% of DOR/ISL patients maintained virologic suppression compared to 90.1% continuing BIC/FTC/TAF (treatment difference -1.2%, 95% CI -6.5, 5.0). The bART switch study showed 92.6% of patients maintaining suppression through 96 weeks on DOR/ISL.
"Over time, people may need to adjust their HIV treatment regimens because of comorbidities, concerns about toxicities, tolerability challenges, or a desire for regimens with fewer medications," noted Dr. Amy Colson, director of research at Community Resource Initiative in Cambridge, Massachusetts. "These 96-week data are encouraging, showing a non-INSTI option like investigational DOR/ISL could offer an important alternative."
Novel Mechanism of Action
Islatravir (MK-8591) represents a novel nucleoside analog that blocks HIV-1 (search) replication through multiple mechanisms, including reverse transcriptase (search) translocation inhibition, resulting in immediate chain termination and structural changes in viral DNA. This unique mechanism positions islatravir as a potential anchor for various two-drug regimens.
"Islatravir blocks HIV-1 (search) replication through multiple mechanisms, including reverse transcriptase (search) translocation inhibition, and could serve as the anchor for a series of two-drug, non-INSTI, daily and weekly treatment regimens," explained Dr. Eliav Barr, senior vice president and chief medical officer at Merck (search) Research Laboratories.
Regulatory Timeline and Future Development
The FDA has established an April 28, 2026 target action date under the Prescription Drug User Fee Act (PDUFA) for the DOR/ISL New Drug Application. The submission is supported by 48-week data from the switch studies, with the new treatment-naïve data providing additional regulatory support.
Beyond daily dosing, Merck (search) is advancing islatravir in multiple combination approaches. The compound is in Phase 3 development with Gilead's lenacapavir as a once-weekly oral treatment (ISLEND-1 and ISLEND-2 trials) and in Phase 2b development with Merck's investigational NNRTI ulonivirine (MK-8507) for weekly dosing.
The company is also developing MK-8527, an investigational once-monthly oral candidate for HIV pre-exposure prophylaxis, currently enrolling in two Phase 3 trials (EXPrESSIVE-11 and EXPrESSIVE-10) across multiple global regions.
These developments represent Merck (search)'s continued commitment to HIV research spanning four decades, focusing on treatment simplification and addressing evolving patient needs in HIV care management.