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Newest ART
The Newest 2-Drug Option in ART

Released: May 12, 2026

Chloe Orkin
Chloe Orkin, MBChB, FRCP, MD
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Key Takeaways
  • Single-tablet, 2-drug ART regimens include dolutegravir/lamivudine, dolutegravir/rilpivirine, and the newly approved doravirine/islatravir. 
  • Two phase III clinical trials provided evidence of doravirine/islatravir noninferiority to standard-of-care oral ART, and specifically BIC/FTC/TAF, in people living with virologically suppressed HIV.

The advent of modern antiretroviral therapy (ART) has brought about unprecedented opportunities for optimization of HIV treatment. Now, the goal of treatment is no longer limited to maintaining virologic suppression but tailoring ART to meet individual needs and preferences to ensure the utmost quality of life for people living with HIV.

Regimen simplification to reduce pill burden and long-term cumulative drug exposure has become a central goal of HIV management. The modern paradigm prioritizes once-daily, single-tablet regimens whenever feasible, and the use of newer strategies, such as long-acting injectables and 2-drug regimens, is becoming increasingly widespread.

Single-tablet, 2-drug regimens that are available include dolutegravir/lamivudine (an integrase strand transfer inhibitor [INSTI] plus nucleos(t)ide reverse transcriptase inhibitor), dolutegravir/rilpivirine (an INSTI plus nonnucleoside reverse transcriptase inhibitor [NNRTI]), and the newly approved doravirine (DOR)/islatravir (ISL), which is an NNRTI plus nucleoside reverse transcriptase translocation inhibitor. DOR/ISL was recently approved for treatment of HIV among people who have virologically suppressed HIV and no history of virologic failure, and it has been evaluated in several phase III clinical trials, including 1 study in people who are treatment-naïve and 2 switch studies in people with viral suppression. The 96-week results of these studies, which provided evidence for this recent approval, were presented at CROI 2026.

The Evidence
The first of these studies, MK-8591A-051, was an open-label switch study from any oral ART and included a population more representative of the global population living with HIV than typical clinical trials. Approximately 40% were assigned female sex at birth, approximately 45% were Black, and the median age was 51 years. Most people (64%) switched from an INSTI regimen, and approximately 30% switched from an NNRTI-based regimen. To enter the study, participants had to have virologic suppression for at least 3 months on ART, with no prior virologic failure or resistance to DOR, and no chronic hepatitis B virus (HBV) infection. 

The headline findings from MK-8591A-051 are that DOR/ISL was noninferior to continuing the baseline ART regimen at Week 96. Those who switched to DOR/ISL at Week 48 also maintained high levels of suppression, compared with those who switched earlier. There was no emergent resistance to DOR/ISL. Tolerability was good with low rates of adverse event–related discontinuation. CD4+ cell count and total lymphocyte count remained stable. 

The second study, MK-8591A-052, had the same inclusion criteria as MK-8591A-051 but was double blinded, and it compared DOR/ISL to maintaining bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF). The participants were slightly younger (median age: 47-48 years), with fewer females assigned at birth (~21%) and mainly White ethnicity (~60%). In terms of efficacy, DOR/ISL was noninferior to maintaining BIC/FTC/TAF at Week 96.

One participant discontinued treatment because of confirmed virologic failure with emergent resistance (H221Y, M230L, and L234I). Of interest, M184V was detected at baseline (on proviral DNA) in this individual. There were also 3 cases of low-level HBV viremia without antigenemia or elevated transaminases and 4 cases of acute HBV infection (both with negative hepatitis B core antibody and hepatitis B surface antibody at baseline). There was no difference in weight change at Week 96.

My Interpretation
These trials provide evidence of high efficacy for DOR/ISL. Resistance occurred infrequently, even among those with prior exposure to NNRTIs. People with resistance to DOR are not candidates for the regimen. Tolerability was generally good. However, there was no benefit for DOR/ISL in terms of weight vs BIC/FTC/TAF. Guidelines are clear that there is no clear evidence to suggest that you should start any particular regimen to avoid weight gain or switch to anything. Unfortunately, we are in a situation where we need to advise people to try and avoid weight gain and to manage it when it happens using alternative agents, but antiretrovirals are not the way to go.

People who are not candidates for this new regimen include those with HBV, similar to the other 2-drug ART regimens. Outstanding questions include more longevity of data and real-world evidence.

It is important that providers discuss novel therapies with the people we take care of. As guidelines recommend, we should review new options with people to ensure that they are on the right drug. We should inform them of novel therapies utilizing shared decision-making. It is important that we keep communicating that the field is progressing with new drug options.

Your Thoughts
How do you think the approval of DOR/ISL will affect your clinical practice? What do you think of 2-drug regimens becoming more widespread for HIV treatment? Leave a comment to join the discussion!

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