First Non-INSTI, Tenofovir-Free Regimen DOR/ISL Gains FDA Approval for HIV

The FDA has approved a new HIV treatment option from Merck, marking a notable development in antiretroviral therapy for people living with HIV.¹ The newly approved regimen is a fixed-dose combination of doravirine and islatravir (DOR/ISL; Idvysno), and is indicated for adults with virologically suppressed HIV-1 who have no history of treatment failure and no known resistance to DOR.

The once-daily, single-tablet regimen combines 100 mg of DOR with 0.25 mg of ISL and is intended to replace a patient’s current antiretroviral therapy if the patient is stable and meets eligibility criteria. According to the company, the regimen is the first and only complete 2-drug therapy that is both non–integrase strand transfer inhibitor (non-INSTI)–based and tenofovir-free, offering a new alternative for patients who may benefit from avoiding certain drug classes or reducing treatment complexity.

The FDA’s decision is supported by data from a pair of phase 3 trials demonstrating noninferiority to standard 3-drug regimens, including bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy; Gilead Sciences). In the double-blind MK-8591A-052 (trial 052; NCT05630755), 1% of participants who switched to the DOR/ISL regimen had HIV-1 RNA levels of 50 copies/mL or greater at week 48, compared with 1% of those who remained on bictegravir/emtricitabine/tenofovir alafenamide (treatment difference, 0.9%; 95% CI, –1.9% to 2.9%). Viral suppression rates remained high, with 92% of participants on the 2-drug regimen maintaining HIV-1 RNA levels below 50 copies/mL versus 94% in the comparator group.

In the open-label MK-8591A-051 trial (trial 051; NCT05631093), which evaluated switching from a variety of baseline regimens, 1% of patients receiving DOR/ISL had viral loads of 50 copies/mL or greater at week 48, compared with 5% among those who continued baseline antiretroviral therapy (treatment difference, –3.6%; 95% CI, –7.8% to –0.8%). Viral suppression rates were 96% for those who switched to the 2-drug regimen and 92% for those who remained on prior therapies.

“Idvynso is the first non-INSTI, tenofovir-free, two-drug regimen to demonstrate non-inferior efficacy to standard oral antiretroviral regimens, including Biktarvy,” Amy Colson, MD, MPH, director of research at Community Resource Initiative, Boston, Massachusetts, said in a statement. “This makes Idvynso a potential alternative for people with virologically suppressed HIV who may need to switch their treatment.”

In an earlier interview with The American Journal of Managed Care^®, Colson explained that the new therapy could help patients who are in need of a treatment that’s both highly effective and carries a lower risk of long-term toxicity, especially as the population of people living with HIV continues to age.² Many individuals achieve stable viral suppression on their current regimens but may want or need to switch treatments, whether due to tolerability concerns or potential interactions with newly prescribed medications.

“DOR/ISL is a simple regimen, containing less drugs from different families and/or with different mechanisms of action from the current available ones, and has potential to be a highly efficacious and safe regimen for people living with HIV infection who may need or want an [INSTI-]sparing regimen,” she said.

The approval comes as HIV care continues to evolve beyond viral suppression alone, with increasing emphasis on long-term health, comorbidities, and treatment burden.¹

From a pharmacologic standpoint, the regimen introduces ISL, a next-generation nucleoside reverse transcriptase inhibitor (NRTI) with multiple mechanisms of action, including inhibition of reverse transcriptase translocation and delayed chain termination. DOR, a non-nucleoside reverse transcriptase inhibitor (NNRTI), has an established safety and efficacy profile and complements ISL’s antiviral activity.

Safety findings from the phase 3 trials indicate that the DOR/ISL combination has a tolerability profile comparable to existing therapies. In trial 052, 3% of participants receiving the 2-drug regimen discontinued treatment due to adverse events, compared with 2% in the DOR/ISL group. In trial 051, discontinuation rates were 0.5% for the DOR/ISL group and 2% for baseline regimens. The most commonly reported adverse events—generally occurring in 2% or fewer patients—included diarrhea, dizziness, fatigue, abdominal distention, and headache.

However, important safety considerations remain. Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been associated with DOR-containing regimens. The combination is contraindicated with strong CYP3A enzyme inducers and should not be used with lamivudine or emtricitabine, as such interactions may reduce treatment effectiveness or increase the risk of resistance.

The clinical trials included a diverse population of participants, with ages ranging from 18 to over 80 years and meaningful representation across sex and racial groups. Approximately 11% of participants were aged 65 years or older, and outcomes were consistent across demographic subgroups.

The regimen is expected to become available in US pharmacies after May 11 and will be supported by patient assistance programs to improve access and affordability.

The approval of the DOR/ISL combination adds to a growing array of treatment strategies designed to simplify HIV management while maintaining viral suppression. As clinicians increasingly tailor therapy to individual patient needs, the introduction of a 2-drug, non-INSTI, tenofovir-free option may offer an important alternative for patients seeking to transition from more complex regimens.

References

1. FDA approves Merck’s once-daily IDVYNSO (doravirine/islatravir) for adults with virologically suppressed HIV-1. News release. Merck & Co. Published April 21, 2026. Accessed April 22, 2026. https://www.merck.com/news/fda-approves-mercks-once-daily-idvynso-doravirine-islatravir/
2. Shaw ML, Colson A. Advancing HIV care with doravirine and islatravir: Q&A with Amy Colson, MD, MPH. AJMC^®. March 12, 2025. Accessed April 22, 2026. https://www.ajmc.com/view/advancing-hiv-care-with-doravirine-and-islatravir-q-a-with-amy-colson-md-mph