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ART Simplification for HIV
The Near Future of Regimen Simplification for Heavily Treatment–Experienced HIV

Released: April 28, 2026

Charlotte-Paige Rolle
Charlotte-Paige Rolle, MD, MPH
Paul E. Sax
Paul E. Sax, MD
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Key Takeaways
  • Several new simplification options are on the horizon for the management of multidrug-resistant HIV among heavily treatment–experienced people.

The “soon to come” availability of novel oral single tablet regimens and long-acting injectables may allow for regimen optimization in a group of people with HIV who have historically needed to take complex combination regimens to achieve and maintain virologic suppression. 

Imagine a 61-year-old person who has had HIV for 35 years. In the past, he participated in several early HIV clinical trials, which included some for the older nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). He has also had some adherence barriers in the past and experienced virologic failure with prior regimens. He has documented 3-class HIV resistance (NRTIs, NNRTIs, PIs) and is currently suppressed on a regimen of darunavir/cobicistat and dolutegravir.

He is currently employed as a long-distance truck driver and frequently has to stop for bathroom breaks owing to chronic diarrhea, which he attributes to his HIV medications.  His other medical conditions include hypertension, type 2 diabetes, and mixed hyperlipidemia and obesity with a BMI of 33 kg/m2.  He is on lisinopril/hydrochlorothiazide, metformin, and atorvastatin.  How might you manage this case in the near future?

Recent data highlighted the efficacy and safety of several new agents in the pipeline that may offer heavily treatment–experienced people like him an opportunity for clinically meaningful regimen optimization. Here are our thoughts on how they may change the landscape of HIV treatment.

Emerging 2-Drug Regimens: Yes or No for Heavily Treatment–Experienced People?

Charlotte-Paige Rolle, MD, MPH:
The 48-week results from ARTISTRY-1 are particularly exciting for heavily treatment–experienced people, in whom we observed noninferior efficacy and good safety with the investigational combination of bictegravir/lenacapavir compared to remaining on a complex regimen.

Paul Sax, MD, FACP, FIDSA:
I agree, and we also saw something that we see in almost all open-label switch trials: more discontinuations with the switch arm than with the stable background regimen (in this case, 1.6% vs 0.5%). That is what's commonly referred to as ascertainment bias. People who are on a stable regimen, when they switch, if they have any kind of side effects at all, they're going to blame it on their new regimen. 

You can see important information about side effects in the companion ARTISTRY-2 study, which was a double-blinded switch study comparing bictegravir/lenacapavir to bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed people. Both regimens were really effective, but there was no difference in discontinuations due to adverse events, 1.6% in each arm. 

There was also a beneficial effect on lipids in the bictegravir/lenacapavir arm of ARTISTRY-1, which you would expect in people coming off boosted PIs, or boosted anything. 

In fact, 1 of the study participants told me that this study changed his life. On his original complex boosted PI regimen, he had diarrhea and a bad lipid profile. After switching to a single pill, he couldn't be happier.

Charlotte-Paige Rolle, MD MPH:
This investigational combination could be a game changer for many of my patients: approximately 10% of my clinic population is “heavily treatment experienced” with multidrug resistance.  They are not candidates for any of the available single-tablet regimens and cannot take injectable cabotegravir/rilpivirine, often due to preexisting rilpivirine resistance, so I am thrilled to see these newer oral options in the pipeline for them.

Paul Sax MD, FACP, FIDSA:
Another combination that we recently heard about was the 1-pill tablet of doravirine/islatravir. Although this demonstrated noninferiority to baseline antiretroviral therapy in 2 randomized clinical trials, I expect it will have limited utility in this heavily treatment–experienced population for 2 reasons: first, many of these patients will have the M184V mutation, which confers resistance to lamivudine and emtricitabine and decreases the activity of islatravir. Second, some patients with NNRTI resistance are already resistant to doravirine. One of the notable aspects of the clinical trials was that participants who were inadvertently enrolled with baseline resistance to doravirine ended up with virologic failure.

Emerging Long-Acting Directions

Charlotte-Paige Rolle, MD MPH: 
What about emerging long-acting injectables for those who struggle with oral antiretrovirals and cannot take cabotegravir/rilpivirine?

Paul Sax MD, FACP, FIDSA:
The phase III clinical trial of lenacapavir, teropavimab, and zinlirvimab is about to launch. This is twice-yearly lenacapavir in combination with 2 parenteral broadly neutralizing antibodies, teropavimab and zinlirvimab, to maintain virologic suppression in adults living with HIV.

I'm a bit of a skeptic when it comes to broadly neutralizing antibodies for HIV therapy, but this particular strategy had very good results in phase II studies comparing it to oral standard of care, and I expect we'll soon see phase III studies comparing it to long-acting cabotegravir/rilpivirine. This is yet another injectable that may eventually be an option for treatment-experienced people whose resistance profiles preclude the use of our currently available long-acting injectables. 

Your Thoughts
How do these data potentially affect your management of the patient described in the case above? Leave a comment to join the discussion!

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