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ART simplification
ART: Not One Drug Fewer Than Necessary, And Not One More

Released: August 10, 2026

Luis Buzón Martin
Luis Buzón Martin, MD
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The 1996 International AIDS Conference in Vancouver marked a turning point in the history of HIV. Triple antiretroviral therapy (ART) transformed an almost invariably fatal infection into a chronic, manageable disease. Three drugs saved millions of lives and, understandably, became much more than a treatment strategy: it became a principle. For many years, that principle served us extraordinarily well. But medicine cannot allow even its greatest successes to become permanent dogmas. The question is never whether a therapeutic paradigm was right in the past. The question is whether it remains necessary today.

From Vancouver to VOGUE
The possibility of treating HIV with 2 drugs did not emerge yesterday. It began with early studies combining a boosted protease inhibitor with lamivudine and became clinically persuasive with dolutegravir-based regimens. GEMINI, TANGO, SALSA, SWORD, STAT, and PASO-DOBLE progressively dismantled the assumption that virologic robustness necessarily depends on maintaining 3 active drugs. Long-acting cabotegravir plus rilpivirine extended that principle beyond daily oral therapy.

Therefore, VOGUE, a recent randomized, open-label study that compared first-line treatment of HIV with dolutegravir/lamivudine (DTG/3TC) vs bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), reveals no sudden or unexpected truth. To me, its importance is that it brings a decade of evidence to its logical conclusion. It may be the last nail in the coffin of the old assumption that 3 drugs must remain the default, simply because 3 once represented security.

VOGUE was the first direct comparison of ART initiation with DTG/3TC vs BIC/FTC/TAF, the contemporary 3-drug standard for initial ART. Participants started treatment regardless of their HIV-1 RNA or CD4+ cell count and before resistance results were available. At Week 48, DTG/3TC was noninferior to BIC/FTC/TAF: Viral suppression occurred rapidly in both groups, confirmed virologic withdrawal was equally uncommon, and no treatment-emergent resistance was identified among participants with evaluable samples.

Advanced Infection
The fact that participants in VOGUE had a wide range of CD4+ counts and HIV-1 RNA levels is particularly relevant to this discussion. At baseline, 16% of participants had fewer than 200 CD4+ cells/mm³, and another 16% had plasma HIV-1 RNA levels of at least 500,000 copies/mL. These results inevitably connect VOGUE with DOLCE, which showed similar efficacy of initial ART with a DTG-based 2-drug regimen vs a standard-of-care 3-drug regimen in people with low CD4 counts and high HIV-1 RNA levels. Together, these studies address one of the most persistent concerns about 2-drug therapy: its potency in advanced infection.

Overall, VOGUE affirms the noninferiority of DTG/3TC compared to a modern 3-drug regimen in a broad range of individuals. I believe this study should be interpreted as the climax of this story, or the point at which any remaining resistance towards using 2-drug regimens as initial ART for people with advanced HIV infection becomes increasingly difficult to sustain.

However, these data do not suggest that every person with HIV should receive a 2-drug regimen. People with chronic hepatitis B infection, clinically relevant resistance, drug intolerances, and certain individual circumstances still require different strategies. Good medicine has never consisted of replacing one universal rule with another. However, considering the full clinical equation, the evidence supports 2-drug regimens for many, if not most, people living with HIV.

For Life
HIV is now a chronic infection that we can control but cannot cure. A person starting treatment today may remain exposed to ART for 40 or 50 years. At the same time, the population living with HIV is growing older. As this population advances in years, age-associated comorbidities, such as hypertension, cardiovascular disease, diabetes, renal impairment, osteoporosis, cancer, and polypharmacy, become supplementary aspects of routine HIV care. The therapeutic decision made at diagnosis is therefore not merely about achieving an undetectable viral load next month. It is also about the cumulative burden of medications—for HIV and for separate conditions—over an entire lifetime.

Modern antiretroviral drugs are highly effective and generally very safe. Nevertheless, no pharmacologic exposure is entirely neutral. Medicine has repeatedly shown that uncommon or cumulative toxicities may become visible only years after a drug enters routine use, sometimes long after registration trials have ended. Abacavir and tenofovir are good examples of that. We cannot predict every possible long-term consequence of every molecule. What we can say is that a drug that is not taken cannot cause toxicity.

That does not prove that removing a third drug will automatically produce measurable clinical benefit in every individual. It does, however, establish a basic medical responsibility: to me, when 2 drugs achieve the necessary virologic objective, continued exposure to a third should require a specific reason. Once chronicity, ageing, lifelong therapy, and cumulative exposure are placed in the same equation, simplification no longer appears to be therapeutic minimalism. It becomes therapeutic precision. The aim is not to prescribe fewer drugs for the sake of prescribing fewer drugs, but to avoid prescribing more than the patient needs.

Necessary Numbers
A change like this is not expensive or technologically complex, nor does it require new infrastructure. It primarily requires us to reconsider the burden of proof. For years, 2-drug therapy had to justify why it was sufficient. The accumulated evidence suggests to me that, in eligible people, the third drug should justify why it is necessary.

Vancouver taught us that 3 drugs could save lives. The studies that followed taught us that, for many people, 2 can preserve everything that matters. The next major switch in HIV treatment may therefore need to occur not in the prescription, but in our mindset: 2 drugs whenever 2 are enough, and 3 only when 3 are genuinely needed.

Your Thoughts
For perspectives on making decisions between 2- and 3-drug regimens, join me and my colleagues, Pedro Cahn, MD, PhD, and Charlotte-Paige Rolle, MD, MPH, for our free virtual webinar on September 17 or 29. Bring your questions or comments for us to discuss, or leave a comment below!

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