Immunotherapy Offers a New Avenue in HIV Management
Researchers are cautiously optimistic about a novel immunotherapy approach that could one day reduce or even eliminate the need for daily HIV medications. In a first-in-human Phase 1b trial, budigalimab, a monoclonal antibody that blocks the programmed cell death protein 1 (PD-1) pathway, was tested in people living with HIV. Published in Nature Medicine, the study found the treatment to be safe at low doses and, for a subset of participants, associated with delayed viral rebound after stopping standard antiretroviral therapy (ART).
The PD-1 pathway acts as a brake on immune T cells. In many people with HIV, this brake keeps immune responses weakened, allowing the virus to persist. By inhibiting PD-1, budigalimab aims to re-energize T cells so they can better control HIV. While not a cure, this strategy could pave the way for periods of drug-free viral control for some individuals.
What the Trial Found
The randomized, placebo-controlled study enrolled 41 participants across 11 sites (nine in the U.S., one in Canada, one in Australia). The trial consisted of two stages with escalating dosing designed to maximize safety while evaluating immune responses. In stage 1, participants on suppressive ART received budigalimab at two different low doses or placebo, followed by ART interruption and close monitoring. Stage 2 exposed a separate group to four doses of budigalimab over six weeks, with ART interrupted as well.
Adverse events were generally mild to moderate, supporting a favorable safety profile for these low, cancer-dosed regimens. Importantly, six of the eleven participants in stage 2 who received budigalimab experienced a delayed viral rebound, and two remained off ART for more than six months without viral resurgence. No similar benefit appeared in the placebo group.
Remarkably, some participants maintained viral control even after the anti-PD-1 drug was no longer detectable in their bodies. This observation hints at a potential reshaping of the immune response—an improvement in the immune system’s long-term ability to keep HIV in check, beyond the presence of the drug itself.
Context and Implications
“For the first time, we’ve tested a cancer immunotherapy drug at a low dose in people living with HIV to see if it could help control the virus without daily ART,” said Dr. Jean-Pierre Routy, the study’s principal investigator. He noted that the treatment’s tolerability and the signals of long-term viral control are encouraging, even though this is not a cure and the response was incomplete, occurring only in a subset of participants.
Historically, HIV research has pursued strategies to “reinvigorate” exhausted T cells through PD-1 blockade. This Phase 1b trial advances that effort by demonstrating feasibility and safety in humans living with HIV, albeit at doses much lower than those used for cancer therapy. The findings open the door for combination approaches—pairing anti-PD-1 therapy with other immunomodulators or therapeutic vaccines—to broaden responsiveness and durability of viral control.
Next Steps and Future Considerations
Experts emphasize that larger, more diverse studies are needed to confirm these results and understand who might benefit most. The current trial population skewed toward cisgender men, underscoring the need for broader inclusion of women and other groups to evaluate hormonal and genetic factors that could influence outcomes.
Dr. Routy also noted that future work may explore integrating PD-1 blockade with additional immune-modulating strategies to boost the likelihood of achieving sustained, drug-free control for a broader segment of people living with HIV.
A Montreal Connection to a Global Effort
The PD-1 pathway was identified by Tasuku Honjo, a Nobel laureate, and Montreal researchers Rafick-Pierre Sékaly and Lydie Trautmann, along with Dr. Routy, laid early groundwork by showing PD-1 blockade could reactivate HIV-specific immune responses in the lab. Their foundational work supported the transition from concept to clinical testing in humans.
About the Study
The Nature Medicine paper, “Budigalimab, an anti-PD-1 inhibitor, for people living with HIV-1: a randomized, placebo-controlled phase 1b study,” reports on a trial sponsored by AbbVie. The study’s DOI is 10.1038/s41591-025-03993-0. While the results are promising, researchers caution that the approach requires further validation, optimization, and exploration of long-term safety and efficacy before any real-world clinical adoption.
