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Immunologic Benefit Despite Delayed Virologic Suppression
Immunologic Benefit Despite Delayed Virologic Suppression in Multidrug-Resistant HIV: What Is the Significance?

Released: January 06, 2026

Judith A. Aberg
Judith A. Aberg, MD
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Key Takeaways
  • Multidrug-resistant HIV presents unique challenges in achieving virologic suppression.
  • Antiretroviral therapy for multidrug-resistant HIV may offer immunologic benefits even when viral suppression is delayed.

Case Presentation
A 50-year-old male who was diagnosed with HIV in 1995 was referred for management of multidrug-resistant HIV in 2015. His history included stage 2 chronic kidney disease (CKD), thrombocytopenia, hepatitis B virus coinfection, oral hairy leukoplakia, and pneumocystis pneumonia. At presentation, he was receiving tenofovir disoproxil fumarate/lamivudine/etravirine and darunavir/ritonavir, with a CD4+ T-cell count of 1 cell/mm3,  HIV-1 RNA level of 251,036 copies/mL, and platelet count of 30 x 109/L. 

Prior and current resistance testing revealed pan resistance to all nucleos(t)ide reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors, and integrase strand transfer inhibitor resistance mutations including N155H and G140A. A coreceptor tropism assay revealed dual/mixed tropic HIV. He had previously tried an HIV fusion inhibitor but was unable to tolerate the injections.

He was switched to dolutegravir 50 mg twice daily plus fostemsavir 600 mg twice daily and prescribed tenofovir disoproxil fumarate/emtricitabine for management of hepatitis B virus. At Week 24, his HIV-1 RNA levels had decreased to 600 copies/mL and CD4+ T-cell count increased to 56 cells/mm3. Although the HIV RNA levels were not suppressed to <200 copies/mL until Week 60, the CD4+ T-cell count continued to increase. At Week 120, the HIV RNA levels became undetectable and the CD4+ T-cell count was >300 cells/mm3. Of note, his CKD improved to stage 1 and platelet count increased to >100 x 109/L by Week 8 and remained within normal range throughout his care.

Discussion
The primary goal of antiretroviral therapy (ART) is to achieve virologic suppression and CD4+ T-cell restoration. Immunologic nonresponders are at increased risk for AIDS-defining events like malignancies and non-AIDS defining events, despite virologic suppression.  This makes treating multidrug resistant HIV particularly tricky. 

Fortunately, there are now 3 FDA-approved antiretrovirals used to treat multidrug-resistant HIV: fostemsavir, ibalizumab, and lenacapavir. At the time this patient was evaluated, only fostemsavir was available as an investigational agent. Shortly after, a study evaluating ibalizumab was opened, and it allowed fostemsavir to be included as a component of background therapy. However, given the different mechanisms of actions, it is unknown if ibalizumab and lenacapavir would have similar immunologic responses in the setting of delayed viral suppression. Hence, my comments below pertain to fostemsavir alone.

Although the person in this case study took longer to achieve virologic suppression, his immune reconstitution had already begun by Week 24, and his CKD and platelet count had improved even earlier, by Week 8.

I think this case highlights the importance of leveraging the capabilities of drugs approved to treat multidrug-resistant HIV and illustrates that they may provide benefit even if virologic suppression is not immediately achieved—especially if someone has severe immune impairment and significant comorbidities.

Indeed, in the BRIGHTE study of fostemsavir, CD4+ T-cell responses were greater than expected.

Possible Mechanisms for Immune Reconstitution
The mechanisms behind this immunologic benefit in the setting of incomplete virologic response remain under investigation, although the most is currently known about fostemsavir. The active metabolite temsavir binds directly both to membrane- associated and soluble gp120, resulting in a closed inactive state that blocks HIV-1 attachment to CD4+ T-cells and HIV entry.

It also prevents antibody-dependent cellular cytotoxicity from targeting uninfected bystander CD4+ T-cells (mediated by soluble gp120 that was shed by infected cells), thereby preventing their elimination. This is supported by recent data from Benlarbi and colleagues, who studied blood samples from heavily treatment-experienced people receiving ART that included fostemsavir vs those receiving ART that did not include fostemsavir. They reported a significant decline in anti-gp120 CD4i antibodies in the fostemsavir groups, but not in the control groups. This suggests that fostemsavir might not only block viral entry into CD4+ T-cells, but may also prevent the gp120-mediated elimination of uninfected CD4+ T-cells.

Further, in an analysis of the BRIGHTE study from Chen and colleagues, people with delayed vs early viral suppression in response to fostemsavir treatment had higher IL-8 levels at treatment initiation and lower baseline anti-Env IgG titers and CD4+ T-cell counts. They also had greater increases in CD4+ T-cell counts after treatment. 

More studies are needed to understand the mechanisms by which immunologic recovery can occur even in the setting of delayed virologic response. It is also unclear, given their different mechanisms of actions, if ibalizumab and lenacapavir can lead to similar immunologic responses in the setting of delayed viral suppression as fostemsavir. Ultimately, learning more about how these drugs provide immunologic benefit even in the setting of incomplete viral suppression will enhance our ability to individualize ART regimens for maximum clinical benefit.

Your Thoughts
What has your experience been in managing multidrug-resistant HIV? Have you observed immunologic response in the setting of delayed virologic suppression? Please join the conversation by leaving a comment below!

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