Anti-PD-1 Immunotherapy Shows Promise for Drug-Free HIV Control in Phase 1 Trial
Key Insights
A Phase 1 clinical trial of budigalimab, an anti-PD-1 (search) monoclonal antibody, demonstrated safety and potential for long-term HIV (search) control without daily antiretroviral therapy (search).
Six of eleven participants who received treatment in stage 2 experienced delayed viral rebound, with two maintaining viral suppression for over six months after stopping ART.
The low-dose immunotherapy approach targets the PD-1 (search) pathway to re-energize exhausted T cells, potentially enabling the immune system to control HIV (search) independently.
A first-in-human clinical trial investigating an anti-PD-1 (search) immunotherapy for HIV (search) has demonstrated promising results for achieving drug-free viral control, offering new hope for the nearly 40 million people living with HIV worldwide. The randomized, placebo-controlled double-blind Phase 1 study, published in Nature Medicine, found that budigalimab, a monoclonal antibody targeting programmed cell death protein 1 (search) (PD-1), was safe and showed potential for delaying viral rebound after participants discontinued antiretroviral therapy (search) (ART).
Trial Design and Safety Profile
The study enrolled 41 participants across 11 sites in the United States, Canada, and Australia, conducted in two stages with escalating doses. In stage 1, participants received two intravenous doses of budigalimab at 2 mg or 10 mg, or placebo, administered four weeks apart. Stage 2 involved four doses of 10 mg budigalimab or placebo given every two weeks over six weeks.
"For the first time, we've tested a cancer immunotherapy drug—an anti–PD-1 (search) treatment—at a low dose in people living with HIV (search) to see if it could help control the virus without daily antiretroviral medication," said Dr. Jean-Pierre Routy, principal investigator and Senior Scientist at the Research Institute of the McGill University Health Centre.
The treatment demonstrated an acceptable safety profile, with adverse events ranging from mild to moderate, allowing progression to Phase 2 trials. The doses used were significantly lower than those typically administered in cancer therapy, specifically chosen to improve safety and tolerability for people living with HIV (search).
Efficacy Results Show Delayed Viral Rebound
The most encouraging results emerged from stage 2, where six of eleven participants who received budigalimab experienced delayed viral rebound compared to none in the placebo group. Notably, two participants remained off ART treatment for more than six months without viral rebound, suggesting sustained immune control.
"What's remarkable here is that some participants maintained control of the virus even after the anti–PD-1 (search) drug was no longer detectable in their body," explained Dr. Routy. "This suggests that the therapy may help repair and enhance the immune system's ability to keep HIV (search) in check on its own."
Targeting Immune Exhaustion
The therapeutic approach addresses a fundamental challenge in HIV (search) infection: immune exhaustion. In people living with HIV, the PD-1 (search) pathway acts as a "brake" on T cells, leaving them exhausted and unable to effectively control the virus. For nearly two decades, scientists have explored targeting this pathway, with preclinical studies demonstrating that PD-1 inhibitors could re-energize immune cells to fight HIV more effectively.
The PD-1 (search) pathway was originally discovered by Japanese scientist Tasuku Honjo, who received the 2018 Nobel Prize in Physiology or Medicine. Montreal researchers Rafick-Pierre Sékaly, Lydie Trautmann, and Dr. Routy were among the first to demonstrate in 2006 that blocking PD-1 could restore immune responses against HIV (search) in laboratory studies of patient cells.
Clinical Implications and Future Directions
Current antiretroviral therapy (search), while highly effective at suppressing HIV (search) and preventing illness, requires lifelong daily adherence and is not curative. The challenges associated with daily ART include accessibility issues, adherence difficulties due to stigma and side effects, and mental health considerations.
"For antiretroviral therapy (search) to be effective, it must be taken daily—a routine that can be difficult to maintain due to stigma, side effects and mental health challenges," noted Dr. Routy, who is also Professor of Medicine at McGill University and Clinical Director of the Chronic Viral Illness Service at the McGill University Health Centre.
The researchers acknowledged limitations in the current study, noting that most participants were cisgender men, which does not reflect the full diversity of people affected by HIV (search). They emphasized the importance of more inclusive participation in future studies, particularly among women, to determine whether hormonal factors influence treatment outcomes.
Path Forward
While the results represent a significant advancement, Dr. Routy cautioned that "the effect observed in this first trial was partial and limited to a subset of participants. Further studies will be needed to combine this approach with other immunotherapies and to determine which individuals are most likely to respond."
The findings suggest that enhancing the immune system's response through PD-1 (search) inhibition could help maintain viral control in certain individuals, potentially paving the way for periods of drug-free viral control and progress toward a functional cure. The trial was sponsored by AbbVie (search), and the research continues to build on decades of foundational work in understanding HIV (search) immunology and immune checkpoint inhibition.