Dual immune modulators delay, but don’t prevent, HIV rebound after stopping antiretrovirals

A pair of immune-modulating drugs, budigalimab and trosunilimab, appeared to slow viral rebound in about a quarter of people with HIV who stopped antiretroviral therapy (ART), according to study results presented this week at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) in Denver. Some participants eventually saw their viral load rise with further follow-up, however, and development of this combination will not continue.

While antiretrovirals can keep HIV replication suppressed indefinitely, the virus inserts its genetic blueprints into the DNA of human cells, establishing a long-lasting reservoir that is unreachable by the drugs and usually invisible to the immune system, making a true cure nearly impossible. But researchers are exploring numerous approaches that may help keep the virus in remission after stopping treatment, known as a functional cure.

One approach is anti-PD-1 immune checkpoint inhibitors, monoclonal antibodies that block a receptor on T-cells that regulates their activity. People with chronic HIV infection typically have high PD-1 expression and dampened T-cell responses. Widely used in cancer to unleash T-cells against tumours, anti-PD-1 drugs could potentially also “reinvigorate” exhausted cytotoxic T-cells to fight HIV and perhaps reactivate virus from the latent reservoir, Dr Sharon Lewin of the University of Melbourne in Australia explained at her opening lecture on HIV cure science.

At the 2023 European AIDS Conference, researchers reported that the experimental PD-1 inhibitor budigalimab was associated with delayed HIV rebound or sustained low viral load in a majority of people who interrupted antiretroviral treatment in a small pilot study. The results were recently published in Nature Medicine.

At CROI, Dr Ana Gabriela Pires Dos Santos of pharmaceutical company AbbVie presented findings from a phase II randomised controlled clinical trial evaluating budigalimab plus trosunilimab (ABBV-382), a monoclonal antibody that binds to the alpha-4 beta-7 integrin receptor, which promotes viral replication and cell-to-cell spread.

This study enrolled 142 adults living with HIV at 80 sites in 12 countries in Europe, North and South America, Africa and Asia. Most (86%) were men, the mean age was approximately 47 years and they had been living with HIV for about 16 years, on average; 73% were White, 19% were Black 5% were Asian and a third had Hispanic or Latino ethnicity. At study entry, they were on ART with an undetectable viral load for at least a year.  The current mean CD4 cell count exceeded 800, but about half had previously had a level below 500.

The participants were randomly assigned to one of five study arms:

• 10mg budigalimab alone,
• 1600mg trosunilimab alone,
• 10mg budigalimab plus either 800mg,
• 1600mg trosunilimab, or
• a placebo.

The 10mg budigalimab dose is about 25 times lower than the doses used in clinical trials for cancer.

At the start of the study, participants stopped their antiretrovirals in an analytical treatment interruption (ATI). Budigalimab was administered by IV infusion every two weeks until week 6 (four doses total), while trosunilimab or the placebo were given every four weeks until week 8 (three doses total).

The participants were closely monitored with weekly viral load tests during the ATI. The study protocol required that they restart antiretrovirals if they had two consecutive plasma viral load measurements of 100,000 or greater, confirmed viral load of 10,000 or higher for four weeks, viral load of 1000 or higher for six weeks, two consecutive CD4 counts below 350, severe retroviral rebound syndrome or became pregnant. They could also restart treatment upon request at any time. Even low-level persistent viraemia can lead to health consequences, and 1000 is around the level where HIV transmission can occur.

The primary study outcome was the proportion of people who maintained a viral load below 1000 at week 24 without having to restart antiretrovirals. At that point, 24% of people in the budigalimab/low-dose trosunilimab group met the criteria, compared with 10% in the budigalimab/high-dose trosunilimab group, 10% in the budigalimab monotherapy group, 5% in the placebo group (similar to the rate typically seen during ATIs) and 0% in the trosunilimab monotherapy group. The difference between the budigalimab/low-dose trosunilimab and placebo groups was statistically significant. Using a viral load cut-off of 200, the corresponding proportions were 14%, 5%, 10%, 5% and 0%, respectively.

With further follow-up, however, viral control rates decreased in all the active treatment groups. Dr Pires Dos Santos reported that at least two participants were no longer able to maintain control of HIV at 52 weeks. The median peak viral load and the time to viral rebound did not differ between the active treatment and placebo groups.

As a limitation, she noted that five people had detectable levels of antiretrovirals in their blood during the treatment interruption – including three who had used injectable cabotegravir and rilpivirine about a year prior – which could confound results.

Treatment with budigalimab and/or trosunilimab was generally safe, but side effects were common. Across all active treatment groups, 44% of participants experienced treatment-related adverse events and 11% discontinued for this reason. Further, 20% had severe side effects (4% deemed treatment related), 7% experienced immune-related events (all in the arms containing budigalimab) and 12% had adverse effects associated with retroviral rebound syndrome.

Commenting after the presentation, Dr Joseph Eron of the University of North Carolina at Chapel Hill noted that anti-PD1 drugs can cause immune-mediated adverse events even at very low doses. “I think this strategy is not a good one in terms of taking healthy volunteers [living with HIV] and giving them anti-PD1 at any dose,” he said.

Based on these results, “levels and durability of ART-free viral control are not sufficient to offer transformational benefits to people living with HIV and do not justify further development of budigalimab plus trosunilimab,” the researchers concluded. “These findings suggest that further studies of immune-mediated therapy with anti-PD1 agents may require approaches involving novel mechanisms.”

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