First-in-human clinical trial of anti-PD1 medication for people living with HIV confirms treatment safety and shows potential for drug-free viral control.
HIV remains a major global health issue, affecting nearly 40 million people worldwide. Current treatments, known as antiretroviral therapy (ART), are highly effective at suppressing the virus and preventing illness, but they are not curative and must be taken for life.
Now, encouraging results from a Phase 1 clinical trial of an immunotherapy commonly used in cancer offer new hope. Published in Nature Medicine, the randomized, placebo-controlled double-blind study investigated the safety and tolerability of budigalimab, a monoclonal antibody targeting programmed cell death protein 1 (PD-1) in people living with HIV. Not only the findings show that regular short-term low-dose injections of this treatment were safe, but they also suggest that they may have delayed the return of the virus (viral rebound) in some participants after they stopped taking their regular antiretroviral medications.
"For the first time, we've tested a cancer immunotherapy drug -an anti-PD-1 treatment-at a low dose in people living with HIV to see if it could help control the virus without daily antiretroviral medication," said Dr. Jean-Pierre Routy, principal investigator of the study and Senior Scientist in the Infectious Diseases and Immunity in Global Health Program at the Research Institute of the McGill University Health Centre (The Institute). "The treatment was well tolerated, and long-term viral control was observed in about one third of participants who appeared to respond to it. While it is not a cure, these findings suggest that enhancing the immune system's response could help keep the virus under control in certain individuals."
For nearly two decades, scientists have been exploring ways to control HIV without lifelong treatment by targeting the PD-1 pathway. In people living with HIV, this pathway acts as a "brake" on T cells (immune cells), leaving them exhausted and allowing the virus to persist. Before this trial, preclinical studies had shown that PD-1 inhibitors could help release this brake and re-energize immune cells, enabling them to fight the virus more effectively.
"For antiretroviral therapy 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," explains 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. "These drugs may help the immune system control HIV without daily treatment, paving the way for periods of drug-free viral control and, eventually, a functional cure."
"That said, 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," he adds.
Study highlights
The study involved 41 participants across 11 sites - nine in the United States, one in Canada (at The Institute's Centre for Innovative Medicine) and one in Australia - and was divided into two stages. Lower doses were used at stage 1, and preliminary data from stage 1 were used to inform dosing in stage 2.
Adverse events were mild to moderate, allowing the trial to move to Phase 2. The low doses used in the study-much lower than those typically given in cancer therapy-were chosen to improve treatment safety and tolerability for people living with HIV.
Results showed that six of the eleven participants who received the treatment in the second stage of the study had a delayed return of the virus, and two remained off ART treatment for more than six months without viral rebound. No participants in the placebo group experienced this benefit.
"Current HIV treatments and investigational antibody-based therapies only work while the drugs are active in the body," explains Dr. Routy. "What's remarkable here is that some participants maintained control of the virus even after the anti-PD-1 drug was no longer detectable in their body. This suggests that the therapy may help repair and enhance the immune system's ability to keep HIV in check on its own."
In stage 1, participants on suppressive ART received two intravenous doses of budigalimab 2 mg (n = 10) or 10 mg (n = 10) or placebo (n = 5) twice, at a 4-week interval. After receiving their last dose at week 4, participants interrupted their ART and were closely monitored.
In stage 2, a separate group of participants received four rounds of four intravenous doses of budigalimab 10 mg (n-11) or placebo (n=5) every two weeks (at day one, at two weeks, four weeks and six weeks). This group paused their ART on day one and was also closely monitored.
The researchers noted that most participants were cisgender men, which does not reflect the full diversity of people affected by HIV. They emphasized the importance of more inclusive participation in future studies, particularly among women, to determine whether hormonal factors influence treatment outcomes.
A promising discovery with Montreal roots
The PD-1 pathway was first discovered by Japanese scientist Tasuku Honjo, who received the 2018 Nobel Prize in Physiology or Medicine for his pioneering work. Building on this discovery, Montreal researchers Rafick-Pierre Sékaly and Lydie Trautmann at Université de Montréal, together with Dr. Routy at The Institute, were among the first, in 2006, to show in HIV patient cells that blocking PD-1 could restore immune responses against the virus in the laboratory. Their findings, followed by successful studies in animal models, laid the groundwork for the clinical research now being tested in humans.
About the study
"Budigalimab, an anti-PD-1 inhibitor, for people living with HIV-1: a randomized, placebo-controlled phase 1b study" by Moti N. Ramgopal, Jacob P. Lalezari, Ana Gabriela Pires dos Santos, Preethi Krishnan, Tanaya R. Vaidya, Fei Zhou, Heide Betman, Patrick Dorr, Nael M. Mostafa, Maria L. Alcaide, Franco Felizarta and Jean-Pierre Routy was published in Nature Medicine.
DOI: 10.1038/s41591-025-03993-0
The trial was sponsored by AbbVie.
Dr. Routy received research infrastructure support from The Institute and the McGill University Health Centre Foundation, as well as the Canadian Institutes of Health Research through the Canadian HIV Cure Enterprise 3.0 (CIHR-BR4-197730).
