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When Is “Good” Not Good Enough? Insights Into Managing Multidrug-Resistant HIV

Released: March 26, 2026

Onyema Ogbuagu
Onyema Ogbuagu, MD, FACP, FIDSA
Charlotte-Paige Rolle
Charlotte-Paige Rolle, MD, MPH
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Key Takeaways
  • The availability of long-acting agents for heavily treatment–experienced people living with multidrug-resistant HIV has provided an opportunity to achieve and maintain viral suppression and experience remarkable immune recovery.
  • This may allow treatment-experienced people living with HIV, including those who are heavily treatment experienced, the option of choosing treatments according to their individualized preferences while facilitating unique opportunities for adherence support by HCPs.

Imagine a person living with HIV, with heavy treatment experience and resistance across 4 antiretroviral classes. They have significant adherence challenges and detectable viremia, with HIV-1 RNA levels of approximately 300 copies/mL. How would you manage this case?

Several newer agents—lenacapavir, ibalizumab, and fostemsavir—are available for use in heavily treatment–experienced people living with multidrug-resistant HIV. Recent data, including some from CROI 2026, highlighted long-term clinical outcomes from real-world cohorts with these agents. Here are our thoughts on their potential implications.

Onyema Ogbuagu, MD, FACP, FIDSA:
I think that the field is ahead of the label when it comes to using long-acting antiretroviral therapy for individuals with multidrug resistance.

Looking at this through the lens of ending the HIV epidemic, these are people for whom, in the past, we would have put our hands up and left them on 1 active drug to keep their HIV-1 RNA as low as possible to preserve the CD4+ cell count from decaying. But now we are seeing incredible success with people whose HIV would have previously been deemedbe untreatable.

Recent real-world evidence illustrates how this approach may work in practice. Rolle and colleagues reported a real-world case series evaluating the combined use of 2 long-acting agents with distinct mechanisms of action—ibalizumab and lenacapavir—in people with multidrug-resistant HIV. Many participants had extensive resistance, with 38% demonstrating resistance across 4 antiretroviral classes, and many had detectable viremia at baseline. Many also faced significant adherence challenges, including pill fatigue, gastrointestinal intolerance, difficulty swallowing medications, drug–drug interactions, and psychosocial instability.

Despite these barriers, most participants experienced virologic suppression and immunologic improvement. And as I pointed out in a recent editorial with William Short, the outcomes reported in Dr Rolle’s case series are consistent with findings from the clinical trials and observational cohorts such as CAPELLA and PROMISE-US, in which individuals with multidrug-resistant HIV achieved or maintained viral suppression and experienced improvements in CD4+ cell counts when these agents were incorporated into optimized regimens.

At CROI 2026, we saw other examples of virologic suppression with long-acting injectable lenacapavir in people with high baseline resistance or multidrug resistance, including a case series from Ward 86 and larger retrospective analyses in the United States and in France.

We cannot always offer heavily treatment–experienced people an entire regimen that is fully long-acting, but we are still able to deploy some of these long-acting agents with a bit of work in mixing and matching—with intramuscular, subcutaneous, oral daily, oral twice daily options—using agents that play well together. Furthermore, we now have long-acting agents that we can deploy into community settings. I think it is a new era, and I think this brings us closer to achieving optimal treatment outcomes for not just some, but everyone.

Charlotte-Paige Rolle, MD, MPH:
I agree that viremia is not acceptable for anyone anymore. The goal for all patients should be viral suppression. And that just was not the case a few years ago, when we might have been content to let heavily treatment–experienced people live with HIV-1 RNA levels of up to 400 copies/mL.

A great example of how the use of these agents has changed the odds of success for our patients can best be seen by looking at data from the PRESTIGIO registry presented at CROI 2026. Over 7 years, viral suppression and immune recovery increased significantly among patients with 4-class resistance. This was attributed to changes in regimen composition, which included more frequent use of newer agents such as fostemsavir and lenacapavir. These recent data really have highlighted the use of these newer agents in unique combinations that have made achieving and maintaining viral suppression for all people living with HIV more possible now than ever before.

Your Thoughts
How will recent studies affect how you approach management of multidrug-resistant HIV, particularly regarding persistent, low-level viral replication? Leave a comment to join the discussion!

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