FAQ for the main findings of the RIVER trial

RIVER TrialThe RIVER Study
Research In Viral Eradication of HIV Reservoirs

Main Findings FAQ
July 2018

 

The RIVER study is conducted by the CHERUB collaboration

Glossary of terms
 
Adverse event An untoward medical occurrence in a participant after being given a medicine, though which is not necessarily causally related
ART Combination anti-retroviral therapy
CD4 T cell An important immune system cell that HIV targets and hides in
CHERUB Stands for ‘Collaborative HIV Eradication of Reservoirs UK BRC’ – a UK network of doctors and patients working to find a cure for HIV infection
Functional cure A state of remission, when the HIV measured in the blood is ‘undetectable’ without the need for ART, and blood tests show no signs that the virus is making copies of itself
Kick and Kill An approach to a functional HIV cure that tries to wake sleeping cells that contain HIV and then to kill them
Primary HIV infection Recently acquired HIV infection
Randomised Controlled Trial A trial of a new treatment that compares participants receiving a new treatment with participants receiving the existing standard treatment (the control). Participants have the treatment they receive selected randomly.
Reservoir Resting CD4 T cells that contain sleeping HIV
RIVER Stands for ‘Research In Viral Eradication of HIV Reservoirs’
Vaccine In RIVER, two anti-HIV vaccines formed the ‘kill’ part of the active treatment: ChAdV63.HIVconsv and MVA.HIVconsv. Together they form a ‘prime-boost’ vaccination.
Vorinostat In RIVER, vorinostat was the ‘kick’ part of the active treatment that was tested. It is from the group of drugs called histone deacetylase inhibitors.

What is an HIV reservoir?

Most of the body’s immune cells are not fighting but are resting or asleep, ready to jump into action. HIV can hide in these resting cells and can do so for years or even decades. ART does not work against this hiding HIV – it only works against HIV in cells that are awake and active. Resting cells with sleeping HIV are called the HIV reservoir.

What’s the difference between having an undetectable viral load, and being cured of HIV?

ART is very effective and reduces HIV viral load to very low levels. For most people within a few months of starting ART, their viral load becomes lower than the level that tests can pick up – this is known as ‘undetectable’. This does not mean that HIV has gone nor that somebody is cured. The HIV is hiding in the reservoir. If ART is stopped, some sleeping cells will wake up and HIV will start replicating. Viral load usually increases quickly and becomes detectable again within a few weeks.

Why was the RIVER trial needed?

The reservoir is one of the reasons that it is difficult to cure HIV, but researchers believe that targeting the reservoir and making it smaller is one way develop a functional cure.

What did RIVER set out to do?

RIVER was the first randomised controlled trial of an HIV cure approach known as ‘kick and kill’. It sought to find out, in people who were recently diagnosed with HIV and taking ART, whether the HIV reservoir could be reduced by using a drug called vorinostat to activate (‘kick’) the reservoir, and anti-HIV vaccines to then ‘kill’ the reservoir. RIVER also tested whether this combination of treatments was safe to use.

Illustration of the four key steps in the RIVER study, as seen at the level of the cell:

What is a randomised control trial?

A trial of a new treatment that compares participants receiving a new treatment with participants receiving the existing standard treatment (the control). Participants have the treatment they receive selected randomly.

What did RIVER compare?

Participants in the trial were divided into two groups: those who received just ART, known as the control, and those who, in addition to ART, received two vaccines and then a course of vorinostat, known as the active group.

Who took part in it?

The study was conducted between 2015 and 2018 and enrolled 60 people diagnosed with HIV within the last 12 weeks, through one of six trial centres in London and Brighton. The average age of participants was 32 years. Women of child bearing potential were excluded from enrolment.

What did it find?

On the key measure it was testing, RIVER found no significant difference in the size of the HIV reservoir between those who were in the active group taking the kick and kill treatment (vorinostat and vaccines) in addition to ART, and those in the control group who took ART alone.

It also found good evidence that the individual drugs and vaccines used in the trial (ART, vorinostat, the two vaccines) had all worked individually as expected and were safe. The puzzle for RIVER investigators is to understand why in the active group they didn’t work together successfully.

How long were participants followed up for?

Participants were followed for 40 weeks after enrolling up to the conclusion of the trial. They will be followed up annually for the next five years.

Why do you think it didn’t work?

These are the main findings for RIVER that are being presented to participants and the research community a few months after they first became available. Further work is ongoing to understand why the kick and kill approach in RIVER didn’t have the expected effect on reducing the HIV reservoir. At this point there are various possible explanations, for example including:
– The kick drug didn’t work in exactly the right way for the immune system to easily recognise the reservoir cells
– The vaccines induced immune system responses but may not have been the right ones
– More time is needed to see an effect than the 18 weeks at which the RIVER trial tested the HIV reservoir levels

Where does this leave the ‘kick and kill’ approach as a potential HIV functional cure strategy?

While the RIVER study results didn’t show a benefit, they do not mean that ‘kick and kill’ won’t work. There are other studies using a similar approach but using slightly stronger ‘kick’ drugs and different vaccines for the ‘kill’. These ongoing studies will help us to understand why the kick and kill approach we used in RIVER didn’t work.

Did anyone have side-effects or adverse events from being on the RIVER trial?

Yes, mild and moderately severe side-effects were recorded for a few participants in both the control and active groups of the study; all of these resolved quickly. The number of adverse events was higher in the active group that received the vaccines and vorinostat. One person has a side-effect that was graded as severe, but this wasn’t thought to be related to the study medications in RIVER. No events were graded very serious (the highest level).

Do the RIVER findings have any consequences for other similar trials taking place now?

The evidence from RIVER is that the medicines used were safe but that they don’t appear to have worked together to produce the hoped-for ‘proof of concept’ of a cure. A number of analyses are ongoing, and these will help the field understand the RIVER results in greater detail. Other trials will hopefully build on this evidence to help develop future HIV cure trials.

What will the RIVER investigators do next?

Firstly, we must try to fully understand the science that we’ve gained from this study, and we must also wait and look at the results from other similar studies when they report. Together this will help us formulate plans for research through the NIHR-supported CHERUB collaboration.

Is an actual cure or functional cure for HIV possible?

Only one person (the ‘Berlin patient’) has been completely cured of HIV, so we know it is possible. But this was a chance occurrence, based on his need for two bone marrow transplants after he developed leukaemia. Some research groups have tried to see if they could repeat this effect by doing a bone marrow transplant on two HIV infected volunteers, but the strategy didn’t work, and they were not cured.

Despite these setbacks, we are committed via the CHERUB network to doing further research to achieve a functional cure in a wider population. We believe that efforts like RIVER are essential this field forward.

Which organisations were involved in the RIVER trial?

The RIVER study is being conducted by the NIHR-supported CHERUB collaboration, an alliance of HIV researchers at Oxford University, Imperial College London, the University of Cambridge, UCL, and King’s College London. There are 6 centres participating in RIVER: Royal Free Hospital, Royal Free London NHS Foundation Trust; St Mary’s Hospital, Imperial College Healthcare NHS Trust; Mortimer Market Centre, Central and Northwest London NHS Foundation Trust; Chelsea and Westminster Hospital, Chelsea and Westminster Hospital NHS Foundation Trust; St Thomas’ Hospital, London, Guy’s and St Thomas’ Hospitals NHS Foundation Trust; and Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust.

Who funded the RIVER trial?

RIVER is funded by the Medical Research Council (Grant ref MR/L00528X/1) in collaboration with support from industry partners. Raltegravir and Vorinostat are manufactured by Merck Sharp and Dohme (MSD). MSD agreed to supply the study drugs free of charge for participants participating in the study. The manufacture of ChAdV63.HIVconsv and MVA.HIVconsv vaccines and all pre-clinical and clinical work to date for these vaccines have been provided free of charge to the RIVER study by Lucy Dorrell and Tomáš Hanke of the University of Oxford utilising their existing MRC grants. GSK own the ChAd vector and have reviewed the RIVER protocol and have approved the use of the ChAdV63.HIVconsv. in the RIVER study.

An animation here explains what the RIVER trial was testing: https://vimeo.com/181012372

Further information about HIV cure research can be found at two independent websites:

• NAM Aidsmap – https://www.aidsmap.com/
• HIV i-base – http://i-base.info/

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