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The Future of ART at CROI 2026
The Near Future of ART at CROI 2026: Long-Acting Agents and 2-Drug Regimens          

Released: March 27, 2026

Eric S. Daar
Eric S. Daar, MD
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Key Takeaways
  • Landmark data from CROI 2026 support the efficacy and safety of 2-drug regimens, including expansion of DTG/3TC to people with high baseline HIV-1 RNA, and developmental combinations of DOR/ISL and BIC/LEN.
  • Breakthroughs in long-acting ART include weekly oral ISL/LEN and broadly neutralizing antibodies with LEN, which may soon provide even more options for infrequent dosing.

Potential Guideline Updates
For several years, first-line therapy across the globe has focused on second-generation integrase strand transfer-inhibitor (INSTI)–based regimens. This includes dolutegravir (DTG) plus tenofovir disoproxil fumarate (TDF) or alafenamide (TAF) and emtricitabine (FTC) or lamivudine (3TC), or bictegravir (BIC)/TAF/FTC.

Another preferred option in many guidelines is DTG/3TC. Although this regimen has only been recommended for those with HIV RNA levels ≤500,000 copies/mL, new data may support expanding DTG/3TC to people with higher baseline HIV-1 RNA.

First, the DOLCE study enrolled people with CD4 <200 cells/uL, many of whom had plasma HIV RNA >500,000 copies/mL. This study demonstrated high efficacy of DTG/3TC, with over 80% of participants achieving viral suppression.

A meta-analysis presented at CROI 2026, including data from 5 studies, further emphasized that DTG/3TC was highly efficacious in people with low CD4+ T-cells and high plasma HIV RNA, similar to DTG-based 3-drug regimens.

Support for Antiretroviral Therapy (ART) Simplification and 2-Drug Regimens
Also at CROI 2026, a much-anticipated trial enrolling treatment-naive people living with HIV compared a novel 2-drug regimen consisting of the non-nucleoside reverse transcriptase inhibitor, doravirine (DOR), plus a novel nucleoside reverse transcriptase translocation inhibitor, islatravir (ISL), to BIC/TAF/FTC.

The study demonstrated noninferiority of the DOR/ISL combination, with >90% achievement of viral suppression in both study arms.

As seen in other trials of BIC/TAF/FTC, there was no emergent resistance to any of the agents in this combination. By contrast, 2 participants experienced virologic failure in the DOR/ISL group, both with emergent drug resistance.

Although both regimens were well tolerated with similar rates of adverse events, there were 2 incidences of drug-related serious adverse events with DOR/ISL: 1 participant experienced a drug reaction with eosinophilia and systemic symptoms, and another experienced drug-induced liver disease that did not meet Hy’s criteria.

Despite this, I think this study supports the use of this novel 2-drug regimen for select individuals who may not be candidates for standard INSTI-based regimens and those who want to avoid other nucleoside reverse transcriptase inhibitors (NRTIs).

Switch in Suppression
There were several important studies conducted in people with virologically suppressed HIV on stable regimens. This included DOR/ISL in people with virologic suppression, who were randomized to remain on standard-of-care ART or switch to DOR/ISL. A related trial included those with virologic suppression on BIC/TAF/FTC who were randomized to remain on BIC/TAF/FTC or switch to DOR/ISL.

Both studies showed comparably high levels of sustained viral suppression with switching to DOR/ISL and with remaining on standard ART. DOR/ISL was well tolerated with rare emergent drug-resistant virus in select participants experiencing virologic failure.

Similar studies, ARTISTRY-1 and ARTISTRY-2, were conducted using another novel, oral 2-drug regimen: the capsid inhibitor lenacapavir (LEN) plus BIC. ARTISTRY-1 enrolled people with virologically suppressed HIV on a “complex regimen” requiring multiple pills or more than daily dosing, while ARTISTRY-2 enrolled people with HIV on BIC/TAF/FTC. In both studies, participants were randomized to continue their current regimen or switch to LEN/BIC.

Both studies reported noninferiority of BIC/LEN in terms of viral suppression, with good tolerance and no emergent drug resistance mutations. This regimen would provide another novel 2-drug regimen for those who cannot take NRTIs with a second-generation INSTI.

Novel Long-Acting Regimens
The last studies I will discuss may offer a breakthrough in the near future with novel long-acting regimens.

The first was a weekly oral regimen of ISL (2 mg) plus LEN (300 mg). Previously reported phase II data compared ISL/LEN once weekly to continued BIC/TAF/FTC in people with virologically suppressed HIV, with 48 weeks of follow-up. At this meeting, Week 96 data were presented after open-label treatment was given to all at Week 48. These results confirmed the earlier findings and reported very few people with HIV-1 RNA >50 copies/mL in the early and late switch groups.

 The regimen was well tolerated with no impact on lymphocytes or CD4 counts, an important finding considering earlier data showing a dose-dependent effect of ISL on these measures. Adverse event profiles were also very good in both study arms and during open-label follow-up. Phase III studies of this regimen are underway.

Finally, there were exciting data on early-stage drugs that might accommodate even less frequent dosing. This included the EMBRACE study using a single broadly neutralizing monoclonal antibody plus long-acting cabotegravir, the former given either subcutaneously or intravenously every 4 months, and the latter intramuscularly every month. This regimen was associated with high rates of virologic suppression through 12 months of follow-up, comparable to those who continued oral therapy.

We also learned of novel drugs with potentially long half-lives: the injectable INSTIs, GS-3242F and VH4524184, and a capsid inhibitor, VH4011499. I anticipate further discussion of these agents at future meetings.

Your Thoughts
What data on HIV treatment do you think will be the most practice-changing in the near future? Leave a comment to join the discussion!

 

 

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