At a Glance
- Unveiled Phase 3 results for once-daily doravirine/islatravir (DOR/ISL) showed non-inferiority to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).
- MK-8591A-053 achieved 91.8% viral suppression at Week 48 vs. 90.6% BIC/FTC/TAF. Excelled in high viral loads (>100k copies/mL: 94% vs. 88%).
- MK-8591A-052/051 maintained 89-97% suppression at Week 96 after switching from BIC/FTC/TAF or baseline antiretroviral therapy (bART). Safety comparable.
- Regulatory Milestone. U.S. FDA set Prescription Drug User Fee Act (PDUFA) target of April 28, 2026, for virologically-suppressed adults.
Written By: Marka Sheshi, PharmD
Reviewed By: Pharmacally Editorial Team
Merck known as MSD outside the United States and Canada, announced results from three pivotal Phase 3 trials for doravirine/islatravir (DOR/ISL), an investigational once-daily oral two-drug regimen for HIV-1. The data were presented in late-breaking sessions at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. DOR/ISL demonstrated non-inferior efficacy versus standard three-drug regimens like Bictegravir/Emtricitabine/Tenofovir alafenamide (BIC/FTC/TAF), with a comparable safety profile, positioning it as a potential Non-Integrase Strand Transfer Inhibitor (INSTI)-based option. Prescription Drug User Fee Act (PDUFA) target action date set to April 28, 2026.
Dr. Eliav Barr, Merck’s SVP of global clinical development and CMO noting islatravir’s multi-mechanism replication block (including reverse transcriptase translocation inhibition) as an anchor for two-drug, non-INSTI regimens daily and weekly with DOR/ISL poised as the first to address evolving HIV treatment needs if approved.
Trial Designs and Results
MK-8591A-053 (NCT05705349) evaluated DOR/ISL (100 mg/0.25 mg) versus BIC/FTC/TAF (50 mg/200 mg/25 mg) in 536 treatment-naïve adults, randomized 1:1 and stratified by screening CD4+ T-cell count (<200 cells/mm³) and HIV-1 RNA (>100,000 copies/mL); 36.8% had baseline HIV-1 RNA >100,000 copies/mL. MK-8591A-052 (n=513, 2:1 randomization) and MK-8591A-051 (n=551, 2:1) tested switches from BIC/FTC/TAF or baseline antiretroviral therapy (bART) in virologically suppressed adults (HIV-1 RNA <50 copies/mL for ≥3 months), with no prior failure or doravirine resistance.
In MK-8591A-053, 91.8% on DOR/ISL achieved HIV-1 RNA <50 copies/mL at Week 48 vs. 90.6% on BIC/FTC/TAF (difference 1.2%, 95% CI: -3.7 to 6.2; p<0.001), meeting non-inferiority. In high viral load subgroups DOR/ISL’s efficacy in challenging cases where baseline HIV-1 RNA exceeded 100,000 copies/mL (94.0% suppression vs. 87.6% for BIC/FTC/TAF) or 500,000 copies/mL (90.3% vs. 84.4%); showed strong responses. Results are published in The Lancet HIV.
In 96 Week, maintenance switch trials MK-8591A-052 (NCT05630755) shows 88.9% (DOR/ISL) vs. 90.1% (BIC/FTC/TAF) reflects durable suppression post-switch. Results are published in The Lancet.
MK-8591A-051 (NCT05631093) Week 96 outcomes shows 92.6% (continuous DOR/ISL) to 96.6% (late-switch from bART); shows excellent durability across regimens with low rebound rates (1.5-1.9%). Results are published in The Lancet.
Safety Profile
Drug-related AEs were similar across arms: 14% (DOR/ISL) vs. 18% (BIC/FTC/TAF) in naïve trial; discontinuations 1.1% vs. 2.2%. In switch trials, AE discontinuations were 3.2% vs. 2.9% (Week 96).
No new signals; immune reconstitution and CD4/TLC changes comparable. Results support NDA for suppressed patients.
Dr. Amy Colson, director of research at Community Resource Initiative (Cambridge, MA), emphasized that aging people living with HIV often need regimen adjustments for comorbidities, toxicities, tolerability, or fewer pills, and the 96-week data support investigational DOR/ISL as a promising non-INSTI alternative.
Mechanism and Pipeline
Islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI), uniquely blocks HIV-1 reverse transcriptase enzyme movement along viral DNA templates, leading to premature chain termination of viral replication and structural disruptions in the DNA offering multiple antiviral mechanisms beyond standard nucleoside reverse transcriptase inhibitors (NRTIs).
Doravirine/islatravir (DOR/ISL) serves as the foundational “anchor” for non-integrase strand transfer inhibitor (non-INSTI) two-drug regimens, avoiding reliance on INSTIs (e.g., bictegravir) to potentially reduce long-term toxicities like bone/kidney effects while simplifying treatment.
Merck’s pipeline extends this: weekly oral DOR/ISL variants are in early development; islatravir combined with Gilead’s Lenacapavir (a capsid inhibitor) is in Phase 3 trials (ISLEND-1/2: NCT06630286, NCT06630299) as a once-weekly option; and MK-8527 (islatravir prodrug) is enrolling in Phase 3 EXPrESSIVE 11 an 10 trials (NCT07044297, NCT07071623) as a once-monthly pre-exposure prophylaxis (PrEP) pill to prevent HIV acquisition.
Reference
Merck Announces Late-Breaking Data from Three Phase 3 Trials Evaluating Doravirine/Islatravir (DOR/ISL), an Investigational, Once-Daily, Two-Drug Regimen for the Treatment of Adults Living with HIV-1 at CROI 2026, 25 February 2026, Merck Announces Late-Breaking Data from Three Phase 3 Trials Evaluating Doravirine/Islatravir (DOR/ISL), an Investigational, Once-Daily, Two-Drug Regimen for the Treatment of Adults Living with HIV-1 at CROI 2026 – Merck.com
DOR/ISL in HIV-1 Antiretroviral Treatment-naïve Participants (MK-8591A-053), ClinicalTrials.gov ID NCT05705349, https://clinicaltrials.gov/study/NCT05705349
A Switch to Doravirine/Islatravir (DOR/ISL) in Participants with Human Immunodeficiency Virus Type 1 (HIV-1) Who Are Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) (MK-8591A-052), ClinicalTrials.gov ID NCT05630755, https://clinicaltrials.gov/study/NCT05630755
A Switch to Doravirine/Islatravir (DOR/ISL) in Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Who Are Virologically Suppressed on Antiretroviral Therapy (ART) (MK-8591A-051), ClinicalTrials.gov ID NCT05631093, https://clinicaltrials.gov/study/NCT05631093
Rockstroh, Jürgen K et al., Fixed-dose daily doravirine (100 mg) with islatravir (0·25 mg) versus bictegravir, emtricitabine, and tenofovir alafenamide for initial HIV-1 therapy: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial, The Lancet HIV, Volume 0, Issue 0, https://doi.org/10.1016/S2352-3018(26)00033-0
Amy E Colson et al, Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial, The Lancet, Volume 407, Issue 10528, 2026, Pages 611-621, https://doi.org/10.1016/S0140-6736(25)01948-8
Chloe Orkin et al, Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on oral antiretroviral therapy: 48-week results of a phase 3, multicentre, randomised, open-label, non-inferiority trial, The Lancet, Volume 407, Issue 10528, 2026, Pages 599-610, https://doi.org/10.1016/S0140-6736(25)01945-2
About Writer
Marka Sheshi | Doctor of Pharmacy
Driven by a deep commitment to clinical excellence, research integrity, and impactful medical writing. With a strong foundation in pharmacotherapy and patient safety, specializes in transforming complex scientific evidence into authoritative, publication-ready content. Passionate about advancing healthcare through precise, evidence-based communication that informs practice, strengthens research visibility, and improves patient outcomes.