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A major clinical trial has shown that an immune-based treatment allows people living with HIV to safely stop daily therapy and could offer a longer-acting alternative treatment.

The RIO Trial, led by researchers at ÌìÃÀ´«Ã½, found that the use of broadly neutralising antibodies (bNAbs) enabled three quarters of participants in the study to stop their standard antiretroviral therapy (ART) for at least 20 weeks compared to those who received the placebo.

A small proportion of people were also able to remain off ART therapy for considerably longer - up to 2 years.

The randomised, placebo-controlled study is one of the most robust of its kind and suggests that long-acting antibody therapies could offer a new way to manage HIV. The researchers caution however that further studies are needed to understand how long these effects last and who is most likely to benefit from the approach.  

Professor Sarah Fidler, Chief Investigator and Professor of HIV Medicine at ÌìÃÀ´«Ã½, said: "This is the first time a bNAb-based therapy has demonstrated viral load control of this duration and magnitude in a randomised placebo-controlled trial. These results open new possibilities for HIV treatment and bring us closer to our goal of finding a cure."

The study, published in The Lancet HIV, was sponsored by ÌìÃÀ´«Ã½ and conducted in collaboration with the University of Oxford and Rockefeller University in New York. The trial was funded by the Gates Foundation, with additional support from the National Institute for Health and Care Research (NIHR) Biomedical Research Centres at Imperial and Oxford. 

What is ART and why is it used?

Antiretroviral therapy (ART) has transformed HIV from a life-threatening condition into a manageable disease. The schedule of treatment can vary depending on person, but treatment is either taken every day (through pills) or one a month (through injections). 

This treatment is recommended for everyone who has HIV and can allow people with HIV to live long and healthy lives as well as reducing the risk of HIV transmission. However, ART must be taken for life which places a huge burden for people living with HIV, as well as health care systems. If ART is stopped, HIV viral loads rapidly return to detectable levels and can cause serious health problems, with the added risk of passing the virus onto partners and infants.

The reason ART cannot cure HIV is because ART cannot eliminate the virus from a group of resting cells called the HIV reservoir. Therefore, new treatments which could safely control the virus without the need for daily medication are an important area of research.

How did the trial work?  

The study was randomised, doubled-blinded and placebo-controlled. Double-blinding means that neither researchers nor the study participants know whether they have received the active treatment or placebo, and a computer was used to randomly allocate which participants received each treatment. 

68 participants living with HIV were recruited onto the trial across the UK and Denmark between 2021 and 2024 and the trial was designed with meaningful input from the HIV community from the outset.  

Simon Collins, HIV community advocate, said: “RIO is the first study to let so many people safely stay off ART for so long. These are exciting results for a study that is still ongoing."

Looking ahead

The results of the RIO trial represent an important step forward in HIV treatment research. Long-acting bNAbs have demonstrated that ART-free viral control is an achievable goal, and further work is underway to build on these findings. 

The RIO trial is still ongoing. A new open-label arm, called RIO Arm C, has recently completed recruitment and is investigating the optimal timing of bNAb administration. This arm will ask participants to interrupt ART on several occasions to measure how long HIV viral load remains undetectable without treatment. Blood samples will also be collected to examine what happens to HIV and the immune system during these treatment interruptions. ART will be restarted when HIV becomes detectable above a pre-specified level.

Further analyses from the RIO trial are also planned, including exploratory work examining changes in the HIV reservoir and immune responses over time, as well as remaining secondary endpoint analyses including long-term viral control and bNAb pharmacokinetics. These findings will be reported in future publications and will help build a more complete picture of how bNAb-based therapies work and which patients are most likely to benefit

Professor John Frater, co-lead investigator and Professor of HIV Medicine at the University of Oxford said: "These bNAbs appear to function in two ways — first, by directly targeting HIV, and second, by working alongside the body's existing immune defences. These data, from the largest placebo-controlled dataset of its kind, represent an important step forward in our understanding of how immune-based therapies could complement existing HIV treatment strategies."

Professor Michel Nussenzweig, Rockefeller University, New York, said: “The RIO trial is a landmark study showing that antibodies can control viremia for prolonged periods of time in the absence of traditional ART therapy. The challenge now is to find ways of further enhancing host immunity to increase the number of individuals that can benefit from this type of therapy.”

Professor Marina Caskey, Rockefeller University, New York, added: “By carefully studying individuals who maintained control of the virus for extended periods of time, we hope to design better therapies with long lasting effects.”

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Infrastructure support for this research was provided by the NIHR Imperial BRC, NIHR Imperial Clinical Research Facility (CRF) and the NIHR Oxford BRC.

The trial is managed by Imperial Clinical Trials Unit

For further information about the RIO trial please visit: www.riotrial.org