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

Today, Merck announced promising top-line results from its phase 3 trial evaluating the once-daily, oral, 2-drug regimen doravirine/islatravir (DOR/ISL) in adults newly diagnosed with HIV who were treatment naive. 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 2 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 2-drug regimen without an integrase inhibitor showing noninferior efficacy and safety when compared with the 3-drug INSTI [integrase strand transfer inhibitor]-based regimen BIC/FTC/TAF in this population,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a statement.¹

In an interview with Contagion earlier this year, Luisa Stamm, MD, PhD, associate vice president of infectious disease clinical research and section head for HIV at Merck, discussed the results of the trial.

Study Specifics

The MK-8591A-053 trial (NCT05705349) enrolled 537 treatment-naive adults and randomly assigned 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 an 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 nonnucleoside reverse transcriptase inhibitor ulonivirine (MK-8507) and is currently in phase 2 development as an oral once-weekly treatment.³

Prescription Drug User Fee Act 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. Press release. Merck. November 19, 2025. Accessed November 19, 2025. https://www.merck.com/news/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-na/

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

3. U.S. 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. Press release. Merck. July 10, 2025. Accessed November 19, 2025. https://www.merck.com/news/u-s-fda-accepts-new-drug-application-for-mercks-doravirine-islatravir-an-investigational-once-daily-oral-two-drug-regimen-for-treatment-of-adults-with-virologically-suppressed-hiv-1-infe/

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