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Each to Their Own: Matching 2DR and 3DR to Patient Profiles

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Released: October 19, 2026

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Starting antiretroviral therapy (ART) as soon as possible, even on the same day as HIV diagnosis, is an important standard in HIV care, supported by the World Health Organization and other guidelines. In this rapid test-and-treat context, is there a role for 2-drug regimens among the spectrum of ART choices?

Jade Ghosn
Jade Ghosn, MD, PhD
Tailoring 2DR and 3DR Starts

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Until recently, first-line antiretroviral therapy (ART) was built almost exclusively on 3-drug regimens. True, the GEMINI 1 and GEMINI 2 trials provided data for first-line ART with a 2-drug regimen, consisting of dolutegravir (DTG) and lamivudine (3TC), but these trials had restrictions on baseline viral load and CD4 cell count. These restrictions prevented us from translating this 2-drug strategy into a test-and-treat approach, as waiting for laboratory results and genotypic resistance results can delay treatment by up to 3 weeks. 

However, the results of the VOGUE study were published this summer. This study directly compared the 2-drug regimen DTG/3TC with the reference 3-drug regimen, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), using a test-and-treat strategy. There was no upper limit for baseline HIV-1 RNA, no lower limit for CD4 cell count, and participants started treatment before resistance test results were available.

At Week 48, the 2-drug regimen was noninferior to the 3-drug regimen, with similar proportions of participants achieving HIV-1 RNA <50 copies/mL, and similar tolerability and immune recovery. Most important for the test-and-treat approach, in those who did not achieve protocol-defined virologic success, no treatment-emergent resistance mutations occurred in either arm.

I think these findings confirm that when we have 2 potent and robust drugs in an ART regimen, a third drug has no added . For example, in their most recent updates, the Department of Health and Human Services (DHHS) guidelines now recommend the 2-drug regimen DTG/3TC regardless of baseline HIV-1 RNA. However, they still exclude 2-drug regimens for rapid start.

Tailoring Starts:
Although the results of the VOGUE study demonstrate the feasibility of a test-and-treat strategy with DTG/3TC, in clinical practice other factors still come into play when deciding what to recommend for rapid ART initiation.

For example, one must assess hepatitis B status before selecting the first-line regimen, as the available 2-drug regimens are not active against hepatitis B virus (HBV). It’s very easy to screen for HBV with rapid finger-stick tests that give results in minutes; you can do this at the same encounter without waiting for other blood test results. If the person is coinfected with HBV, they will need a 3-drug regimen that contains tenofovir.

If you were unable to do a rapid HBV test and instead had to draw blood and wait 2 or 3 days for results, I believe you could still be comfortable starting a 2-drug regimen and then later switching to a 3-drug regimen if the HBV test was positive. The STAT study showed that starting a 2-drug regimen and then switching to a 3-drug regimen was associated with no HBV treatment-emergent resistance.

In addition, more evidence is needed for 2-drug regimens as initial treatment in the setting of advanced HIV with opportunistic infections. Although the DOLCE study reported noninferiority of DTG/3TC compared to 3-drug regimens as initial ART for people with ≤200 CD4 cells/mm3, and the VOGUE study had no lower limit on CD4 cell count, both studies excluded people with opportunistic infections. Ultimately, I don’t think there are enough data yet to support initiating ART with a 2-drug regimen in the setting of advanced HIV with an opportunistic infection or an AIDS-defining condition. 

Finally, if HIV is newly diagnosed during pregnancy, evidence for initiating a 2-drug regimen is insufficient. In this situation, I would favor starting a 3-drug. In fact, the DHHS guidelines on what to start in pregnancy list the 2-drug regimen of DTG/3TC as an alternative regimen, not a preferred regimen.

Two to Three or Three to Two?
Some people may ask whether it is better to initiate ART with a 3-drug regimen and then step down to a 2-drug regimen after 6-12 months. In routine care, however, people often remain on their initial regimen for years. Patients may be reluctant to switch from a regimen they are tolerating well, and healthcare professionals may be reluctant to switch from a regimen that is working well. This is why I believe it’s important to start with the regimen that is best for the person; they will likely continue that regimen for years.

Your Thoughts
How are you individualizing first-line ART decisions, and what factors most influence whether you begin with a 2-drug or 3-drug regimen?

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