Merck’s 2-Drug HIV Regimen Shows Noninferiority to Standard 3-Drug Therapy

Today, Merck announced promising topline results from its phase 3 trial evaluating the once-daily, oral, 2-drug regimen doravirine/islatravir (DOR/ISL) in adults newly diagnosed with HIV and were treatment-naïve. The double-blind, randomized study met its primary goal, showing that DOR/ISL was noninferior to the standard 3-drug regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) based on the percentage of participants achieving viral suppression (<50 copies/mL) at Week 48. Safety outcomes were also positive, with a comparable safety profile between the two regimens.¹

“We are encouraged by the results from this phase 3 trial with DOR/ISL, evaluating the regimen in adults with HIV who have not previously taken antiretroviral treatments. DOR/ISL is the first two-drug regimen without an integrase inhibitor showing non-inferior efficacy and safety when compared to the three-drug INSTI-based regimen BIC/FTC/TAF in this population,” Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said in a statement.¹

Study Specifics

The MK-8591A-053 trial enrolled 537 treatment-naïve adults and randomized participants 1:1 to receive either the investigational DOR/ISL regimen or BIC/FTC/TAF. The double-blind phase will continue through Week 144, with a Week 96 readout planned, followed by an optional open-label extension through Week 240. Islatravir, Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), remains a key component of the company’s HIV research strategy due to its potency and resistance profile.¹

About the Agents

Doravirine was FDA approved in 2018 and is marketed under the brand name Pifeltro. It is a nucleoside reverse transcriptase translocation inhibitor (NRTTI), that was developed by Merck.³

Islatravir was also developed by Merck, and it is an investigational NRTTI that blocks HIV-1 replication by multiple mechanisms including inhibition of reverse transcriptase translocation, resulting in immediate chain termination and induction of structural changes in the viral DNA, resulting in delayed chain termination.²

Separately, islatravir is being studied in combination with Gilead’s lenacapavir in a phase 3 trial as a novel oral once-weekly treatment for HIV. Additionally, Merck’s islatravir is being studied as a combination treatment with the company’s investigational NNRTI ulonivirine (MK-8507), and is currently in phase 2 development as an oral once-weekly treatment.³

PDUFA and Future Data Release

Earlier this year, the FDA accepted Merck's new drug application for DOR/ISL, with a target decision date of April 28, 2026.⁴

Merck plans to present full trial results at a future scientific meeting. “These data support the potential for this regimen to be a meaningful treatment option for virally suppressed people living with HIV who are looking to switch to a new regimen or people who have not previously been on antiretroviral therapy to start treatment," Barr said.¹

References
1.Merck Announces Positive Topline Results from the Pivotal Phase 3 Trial Evaluating Investigational, Once-Daily, Oral, Two-Drug, Single-Tablet Regimen of Doravirine/Islatravir (DOR/ISL) in Treatment-Naïve Adults with HIV-1 Infection. Merck Press Release. November 19, 2025. Accessed November 19, 2025.

2.Doravirine. Wikipedia. January 12, 2025. Accessed November 19, 2025.
https://en.wikipedia.org/wiki/Doravirine.

3.US FDA Accepts New Drug Application for Merck’s Doravirine/Islatravir, an Investigational, Once-Daily, Oral, Two-Drug Regimen for Treatment of Adults with Virologically Suppressed HIV-1 Infection. Merck Press Release. July 10, 2025. Accessed November 19, 2025.

4.Parkinson J. FDA Accepts New Drug Application for Merck’s HIV Treatment, Doravirine/Islatravir. Contagion. July 10, 2025. Accessed November 19, 2025. https://www.contagionlive.com/view/fda-accepts-new-drug-application-for-merck-s-hiv-treatment-doravirine-islatravir