An experimental once-daily combination pill containing doravirine and islatravir (DOR/ISL) has shown comparable effectiveness to the widely used Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) in treating individuals starting HIV treatment for the first time. These findings were recently presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) held in Denver. Updated results from two additional late-stage clinical trials indicate that DOR/ISL maintains viral suppression in individuals switching from standard daily oral antiretroviral regimens.
Merck, the pharmaceutical company behind this investigational treatment, has submitted data from these studies to the Food and Drug Administration (FDA), with an approval decision anticipated by late April 2026. Doravirine, marketed as Pifeltro and also part of the Delstrigo coformulation, is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) known for its high barrier to resistance. Islatravir, is a first-in-class nucleoside reverse transcriptase translocation inhibitor.
The development of islatravir faced challenges in 2021 when some trial participants experienced a decrease in their CD4 T-cell counts. Yet, researchers determined that the dosages used in those trials were too high, and this adverse effect has not been observed in the lower doses used in the current combination pill.
Effectiveness in Switching Treatment
Merck’s ongoing evaluation of the once-daily single-tablet regimen, which includes 100 milligrams of doravirine and 0.25 milligrams of islatravir, is focused on its potential as both a switch option for individuals who are already virally suppressed and as a first-line treatment for newly diagnosed patients.
In the Phase III trials, reported last year, DOR/ISL maintained viral suppression after 48 weeks. One of the trials involved participants already on Gilead Sciences’ Biktarvy (MK-8591A-052), while the other included individuals on various two- or three-drug oral regimens (MK-8591A-051). Participants were randomly assigned to switch to DOR/ISL or continue their current treatment.
Updated results from this year’s conference showed that the combination pill continued to control HIV effectively over two years. In the first study, 88.9% of those randomized to DOR/ISL sustained an undetectable viral load (below 50) at 96 weeks, while 90.1% of those remaining on Biktarvy achieved similar results. In the second trial, 92.6% of participants who were initially assigned to DOR/ISL and adhered to it throughout the study maintained viral suppression at 96 weeks, as did 96.6% of those who switched to DOR/ISL at the 48-week mark.
Long-Term Safety and Tolerability
Further data from these trials, presented at last year’s European AIDS Conference (EACS 2025), indicated that DOR/ISL was associated with minimal changes in weight or body composition and had no clinically significant impact on lipid levels, blood sugar, or insulin resistance. Dr. Amy Colson, an investigator for the MK-8591A-052 trial, emphasized the importance of having treatment options that can accommodate the unique health needs of individuals living with HIV, especially as they age and face other health conditions.
As therapy regimens may require adjustments over time due to comorbidities and tolerability challenges, the data from the 96-week study suggest that the non-integrase inhibitor option of DOR/ISL could offer a valuable alternative.
First-Line Treatment Insights
Merck also revealed preliminary results from the Phase III MK-8591A-053 trial, which compared DOR/ISL to Biktarvy in previously untreated individuals. This trial involved 536 participants across 20 countries, with a diverse population in terms of race and ethnicity. The median age was 32 years, and 75% of participants were men. About half of the participants had HIV-1 subtype B, while 19% had subtype C, and 28% had other subtypes.
At the trial’s baseline, participants had a median viral load of 55,000, with 10% exhibiting very high levels above 500,000. The median CD4 count was 370, with 17% of participants having counts below 200, indicative of AIDS. These baseline statistics highlight the ongoing challenge of late HIV diagnoses and treatment initiation.
Participants were randomly assigned to commence treatment with either DOR/ISL or Biktarvy, both taken once daily, with primary outcomes evaluated at 48 weeks. Results showed that 91.8% of individuals taking DOR/ISL and 90.6% taking Biktarvy achieved an undetectable viral load. Notably, the frequency of drug-related adverse events was comparable between the two groups, with 14.1% for DOR/ISL versus 18.0% for Biktarvy.
Future Directions and Considerations
Both doravirine and islatravir are not effective against the hepatitis B virus (HBV), unlike tenofovir alafenamide in Biktarvy. In the DOR/ISL group, there were three reported HBV infections, but all participants tested negative for active hepatitis B at study entry. This reinforces the necessity of vaccination for those not already immune.
As research continues, initial results from ongoing trials involving islatravir suggest its potential for longer-acting treatment options, including a combination pill with Gilead Sciences’ capsid inhibitor lenacapavir. Merck is also exploring a once-weekly regimen of islatravir combined with the investigational NNRTI ulonivirine.
These promising developments signal a significant advancement in HIV treatment options, particularly for populations with evolving health needs. As the FDA reviews Merck’s submission, the potential for DOR/ISL to become a new standard in HIV care remains a focal point for healthcare providers and patients alike.
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Disclaimer: This article is for informational purposes only and is not intended as professional medical advice.
