The RIO study: Q&A about controlling HIV with bNAbs

21 April 2025. Related: Early access, Conference reports, Cure-related research, CROI 32 San Francisco 2025.

Simon Collins, HIV i-Base

This Q&A is about the RIO study and using immune based treatments as part of HIV cure-related research.

Background

In March 2025, the first results from the RIO study were presented at CROI. [1-4]

The results showed that immune-based treatments called bNAbs could keep viral load undetectable without HIV meds (ART).

RIO also showed that in some people bNAbs can also work like an HIV vaccine. Some people responded so well that they have not needed ART for over a year. These early results are exciting, but we need to see how long this response lasts.

We also need to understand why the bNAbs only worked for some people and not others.

Similar results were also reported in South African women in a study called FRESH. [5, 6]

1. What is the RIO study?

RIO is an HIV study using immune-based treatments. These immune treatments are called bNAbs (pronounced bee-nabs).

The two bNAbs are long-acting 10-1074 and 3BNC117, also called

RIO involved stopping HIV meds after being given the bNAbs. The time off-ART is called an ATI which stands for analytic treatment interruption.

The ATI showed that the bNAbs worked very well for some people but not for others.

The results were one of the most important studies presented at a leading HIV conference called CROI, held in March 2025.

2. Who took part in RIO?

RIO enrolled 68 men who had been diagnosed in early HIV infection and who started early ART. This included:

• Been diagnosed within about six months of becoming HIV positive.
• Having started ART during very early infection.
• Having an undetectable viral load on ART for at least six months.
• Being sensitive to the bNAbs.
• Not have active hepatitis B.
• Agreeing to take part in the ATI.

Why were no women included?

RIO was also open to women, but in the UK women ten to be diagnosed later in infection.

The FRESH study enrolled 20 women from Southern Africa. [5]

See below for more information.

What did the study RIO involve?

Study participants were also tested to check that the bNAbs were likely to work.

• They were then randomised to one of two groups. One group received active bNAbs. The other group received a non-active placebo infusion.
• ART was also stopped.
• Close monitoring included viral load tests every week.
• ART was then restarted after viral load reached a certain level. This was after either being above 1,000 copies/mL for more than 6 weeks or confirmed at above 100,000 copies/mL.
• People in the placebo group then had the chance to use the active bNAbs after their viral load rebounded. They stayed on ART for another six months and then took a second ATI.

What were the main results from RIO?

Several important results were presented at CROI.

• Most people in the placebo group had viral load rebound within a few weeks. Only 3 out of 34 people were still undetectable off-ART at week 20.
• Most people in the active group stayed undetectable for over five months. In this group 25 out of 34 people were still off-ART.
• Access to bNAbs reduced the chance of viral load rebounding by more than 90%. The difference between the two groups was extremely significant, (p <0.0001).
• About 1 in 3 people in the active group (13 out of 34) continued to stay off-ART for 48 weeks and 7 of these 13 were still off-ART after 18 months. By this time there would be no active bNAbs left to be reducing viral load. This is important.
• Some people in the active group continued to have undetectable viral load for much longer than a year. This is also important.
• There were three main responses to bNAbs during the ATI:
  (1) Rapid viral rebound – within a few weeks.
  (2) Slow viral rebound – roughly 16 to 48 weeks.
  (3) Viral load remained undetectable throughout.
• People who had the longest responses to the bNAbs developed stronger immune responses against HIV.
• One person in the active group, had viral rebound after the ATI, but who then became undetectable again without needing ART. This person showed a potential vaccine response to the bNAbs. They have now been off-ART for more than 18 months.
• Two people in the placebo group also stayed undetectable for more than a year. This type of response has been reported un earlier studies too. It shows why the study needed to have a control group.

Who had the strongest vaccine-like response?

The person with the vaccine-like response was a 38-year-old man who was diagnosed in 2017 with viral load of 55,000 copies/mL. He started ART within three weeks.

Several years lates he joined the RIO study where he was randomised to the placebo group.

After four weeks into the first ATI his viral load rebounded to 6225 copies/mL. He then received dual bNAbs and restarted ART for 6 months before a second ATI. This time viral load rebounded after five weeks and remained detectable for 20 weeks but only at low levels (peak 1893 copies/mL).

Viral load then became undetectable to <20 copies/mL and remained this low for 80 weeks. During this time, levels of both bNAbs were too low to be active and HIV couldn’t be detected.

Technically, if this person remains undetectable and researchers cannot find HIV in his body could this be a cure?

Has this person been cured?

Researchers are generally careful and cautious. Even after such a strong immune response it is important to see how long this person stays undetectable.

HIV might still be hiding somewhere in this person. If these cells wake after the vaccine response has stopped, then viral load might still rebound.

Other types of cure studies, including after stem cell transplants, have waited for several years before calling the results a cure. Even then, some researchers prefer to use the word remission.

Stem cell transplants are extremely dangerous though and are only used with untreatable cancer.

RIO used immune-based treatment that are very safe and that could be used by everyone. We still eed to see how long the response with last.

What do the RIO results mean?

The results showed two main things.

1. bNAbs can work as long-acting HIV drugs that only need to be given even six months.
2. bNAbs enabled some people to stay of ART for longer than a year. This involved close viral load monitoring though as part of the study. This was essential to detect early viral load rebound in some people.

How similar was the FRESH study?

The FRESH study was similar to RIO because it involved stopping ART after giving two bNAbs to people who started ART in early infection.

FRESH also reported that some people were able to stay of ART for more than a years.

The main differences include:

• The FRESH study was run in South Africa and enrolled 20 women.
• These women had been diagnosed much earlier than the men in RIO. They also started ART earlier.
• FRESH was a single group study without a placebo or other control group.
• FRESH used two different bNAbs.
• Both studies reported that some participants stayed off ART after the bNAbs had stopped being active against HIV, suggesting a vaccine-like effect.

Future questions

These were exciting results but there are still lots of questions.

• How long with the vaccine effect last?
• Has the person with the longest responses been cured?
• What happens if people have a third bNAb infusion?
• Can bNAbs be dise in different ways.
• Why did the bNAbs work for some people and not others?
• Is there a way to predict who will respond?
• Will bNAbs work for people who were diagnosed later and who started ART later?
• Can the bNAbs test become more accurate.
• Will newer bNAbs be more effective?

What are bNAbs?

Some people have very strong immune responses to HIV. They develop antibodies that are so strong that they can control HIV without treatment.

These antibodies can disable – or neutralise – a broad range of different types of HIV. This is why that are called broadly neutralising antibodies – or bNAbs for short.

Scientists have also found out how to develop some bNAbs into a new type of HIV treatment.

bNAbs are usually given as an infusion at a research clinic. They are currently being studied as HIV treatment, as prevention like PrEP and in cure-related research (like RIO).

Dozens of different HIV bNAbs have already been developed and many more will be discovered in the future.

How do bNAbs work?

RIO showed that bNAbs can work in two different ways.

1. The first way is to directly reduce viral load. This is by working a bit like regular HIV drugs. This was already known.
2. The second way is that they might also like a vaccine. RIO study was the first study to show this vaccine-like effect. This is very exciting.

There are already dozens of different HIV bNAbs. Some bNAbs are stronger than others.  

Many bNAbs are already available in long-acting formulations. So they only need to be taken every 1 to 6 months.

Each bNAb only works for some people. This means taking a test before using them to check they are likely to work. These tests are not yet perfect though, but they are getting better.

Just like antiviral HIV drugs most studies now use combinations of two or more bNAbs. This reduces the chance of developing resistance.

bNAbs have a very good safety profile.

However, they are currently very expensive to develop and manufacture. If effective though, they should become much less expensive.

Further information

It is easy to access or reports or to go directly to the presentations at CROI. [1-4]

The RIO study website includes more details about the study and includes videos of interviews with some of the study participants. [7]

More details are included in the listing on clinicaltrials.gov. [8]

References

1. RIO study: Dual-bNABs keep viral load undetectable off-ART – plus a potential first case of vaccine-like HIV remission. HTB (21 March 2025).
   https://i-base.info/htb/50530
2. Fidler S et al for the RIO Trial Investigators. RIO: A Randomised Placebo-Controlled Study of 2 LS-bNAbs in People Treated in Early HIV. CROI 2025. Late-breaking oral abstract 107.
   https://www.croiconference.org/abstract/3760-2025/ (abstract)
   watch.croiwebcasts.org/2025croi/ap/54102 (webcast)
3. Frater J et al for the RIO Trial Investigators. Sustained Post-Rebound HIV Remission With Enhanced T-Cell Immunity After LS-bNAbs: A Case Report. CROI 2025. Poster abstract 505.
   https://www.croiconference.org/abstract/2238-2025/
4. Altaf M et al for the RIO Trial Investigators. Sustained T Cell–Mediated Immunity After LS-bNAbs in the RIO Trial: A Vaccinal Effect. CROI 2025. Poster abstract 506.
   https://www.croiconference.org/abstract/3809-2025/
5. Two bNAbs enable viral suppression off-ART in African women in the FRESH cohort. HTB (1 April 2025).
   https://i-base.info/htb/50674
6. Ndung’u T et al for the FRESH study. Evaluation of 2 bNAbs Plus Vesatolimod in Early-Treated South African Women With HIV-1 During ATI. CROI 2025. Oral abstract 105.
   www.croiconference.org/abstract/2240-2025 (abstract)
   watch.croiwebcasts.org/2025croi/ap/54100 (webcast)
7. RIO website.
   www.riotrial.org
8. Clinicaltrials.gov. A Randomised Placebo Controlled Trial of ART Plus Dual Long-acting HIV-specific Broadly Neutralising Antibodies (bNAbs). (RIO)
   clinicaltrials.gov/study/NCT04319367