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Enough is Enough: Avoiding Overtreatment in ART

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Released: October 19, 2026

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Years of evidence—and recent changes to the DHHS guidelines—show that a 2-drug regimen can be just as good as a 3-drug regimen for initial ART. So does a reflexive preference for 3-drug ART reflect contemporary evidence or simply decades of clinical habit?

Pedro Cahn
Pedro Cahn, MD, PhD
Enough ART is Enough

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Approximately 10 years ago, the hypothesis of using 2-drug regimens as HIV antiretroviral therapy (ART) to achieve sustained virologic suppression had healthcare professionals (HCPs) appropriately and cautiously asking what this would mean in practice: “Why should I consider 2-drug ART regimens if the evidence is so strong for 3-drug regimens?”

Now, I believe the field has reached the point where we can turn that question around and ask, “Why should I use 3 drugs when I can do the job with 2?"

When Evidence Changes . . . 
I believe that we now have enough evidence for the efficacy of 2-drug ART from pilot studies like PADDLE, ACTG A5353, from initial ART studies like GEMINI-1 and GEMINI-2, and from the ART switch studies like TANGO and SALSA.

More recently, DOLCE addressed an important lingering concern by evaluating dolutegravir (DTG)/lamivudine (3TC) in treatment-naive people living with advanced HIV and CD4+ cell counts ≤200 cells/mm³, including those with very high HIV RNA levels—even as high as 1 million copies/mL. Even in people living with advanced HIV, the efficacy of DTG/3TC was similar to that of 3-drug ART, with no significant difference in virologic response among participants with baseline HIV-1 RNA levels >500,000 copies/mL.

…Practice Should Follow:
Now, the guidelines have caught up with the evidence. In a very recent update, issued September 24, 2026, the US Department of Health and Human Services (DHHS) guidelines removed the previous baseline HIV-1 RNA restriction for DTG/3TC (plasma HIV-1 RNA >500,000 copies/mL). Based on the DOLCE study, DTG/3TC is now recommended among other initial ART options regardless of baseline plasma HIV-1 RNA, provided the other eligibility criteria are met. In other words, the results of DOLCE and the new guidelines support the use of this 2-drug regimen in appropriately selected patients, even in the setting of advanced disease.

Since the evidence for starting 2-drug ART is strong even in advanced disease, what about 2-drug ART for rapid initiation (ie, before results of baseline resistance testing are available)?

This question is addressed by the D2ARLING study. It provides evidence supporting the noninferiority of first-line DT3/3TC vs a preferred 3-drug regimen without baseline resistance testing. To me, these findings suggest that baseline resistance testing might not be a requirement for initiating treatment with DTG/3TC, provided it is in settings with low frequency or suspicion of transmitted resistance to these drugs.

Evidence or Inertia?
What about those who remain cautious of 2-drug regimens? Some healthcare professionals may be a little nervous about 2-drug regimens because, for the last 30 years, experts and guidelines have been saying that HCPs have to use 3 drugs for optimal efficacy. Based on this logic, HCPs may prefer to use 3 drugs for a patient living with advanced HIV or who has high HIV-1 RNA.

If these HCPs are reluctant to recommend initial 2-drug ART, despite the evidence from GEMINI, DOLCE, and VOGUE, I would say, “Okay, start with a 3-drug regimen for 6 months, but do not punish your patient by prescribing lifelong treatment with a drug that they do not need. Switch after 6 months when the patient is undetectable.”

The drug that you do not take cannot harm you, so using fewer drugs for lifelong HIV treatment makes sense. Imagine another scenario requiring lifelong treatment: hypertension. What would you say to an HCP who said, “We can lower your blood pressure with 1 pill, but we used to prescribe 2 pills, so I will recommend 2 pills even though it’s not necessary”?

Consistent with the evidence and with changes to the guidelines, it strikes me that almost every new and investigational ART is a 2-drug regimen. My prediction? In the next 5-10 years, almost every new ART regimen will be a 2-drug combination.

That is why I ask those who default to using a 3-drug regimen why they would use 3 drugs if viral replication can be safely suppressed with 2. Yes, there are 2 situations when a 3-drug regimen containing tenofovir is needed: hepatitis B virus coinfection or previous exposure to long-acting cabotegravir pre-exposure prophylaxis. Other than those 2 situations, I would avoid lifelong exposure to a third drug that is no longer necessary.

Your Thoughts:
With the latest evidence and the new DHHS recommendation, is it time to reconsider when—and why—we default to 3-drug ART?

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