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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:

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

• NAM Aidsmap –
• HIV i-base –

RIVER participants results briefing



20th July 2018

Results of the RIVER trial


Summary of the results

The main study finding: We saw no significant difference in measures of HIV viral reservoir; total HIV DNA or viral outgrowth at weeks 16 & 18 after randomisation between study arms. Whilst this finding is disappointing, it is valuable that we have shown for the first time definitive, unambiguous results.

The results of this study do not mean that HIV cure is not possible. They also do not mean that the kick and kill approach does not work. They mean that taken together, the way and the time at which we measured the HIV reservoir, the vaccination we used in this trial with the dose and length of treatment with vorinostat, had no additional impact on measures of the HIV reservoir over Antiretroviral therapy (ART) alone.

This study had outstanding commitment from the participants with 100% attendance to primary endpoint study visits and no loss to follow-up and 97% adherence to intervention.

THANK YOU!! because without your support, commitment and enthusiasm this study would not have been successful.

There is not enough evidence from this trial to recommend all study participants from the control arm now receive vaccination and vorinostat in addition to their ART.

ART with integrase inhibitor agents (in most cases with 4-drug combination) started close to the time of HIV acquisition was acceptable, well-tolerated and very efficient at controlling viral replication, allowing the body’s immune system to rapidly recover. Whilst we have shown dramatic reductions in HIV viral load and reservoir measures for all people in the trial who started ART very close to the time of HIV infection, based on the results so far, we cannot recommend interrupting ART.

The tests we have available to measure the HIV reservoir are constantly improving but are still not perfect. It could be that we measured the outcome (at 16-18 weeks) too soon after ART was started or too soon after the intervention. We would very much like to continue to follow up all study participants to see if there is a delayed impact on viral reservoir over time.

The vaccine and vorinostat as used in this study design were safe.

Both the vaccine and vorinostat worked as expected. The measured T-cell responses to HIV were significantly higher in the participants who had the vaccinations compared to the control. The vorinostat worked to alter gene expression, to a level similar to that previously reported 2 hours after dosing.

As ART is so effective, this study highlights the importance of having a control arm when measuring the impact of any novel intervention on measures of HIV reservoir. All future trials in HIV cure should compare the outcomes to a control ART only arm. The risks vs benefits of taking new medication must be balanced against the effectiveness and safety of current ART.

This document describes the results of the study. If you have any questions about it, please speak to your doctor or research nurse.

The following pages explain the trial process and results in more detail.

What the trial set out to do:

The RIVER trial was designed to test whether the idea of “kick and kill” might work as a way of reducing the size of the HIV reservoir. Specifically, RIVER is the first randomised study designed to compare the effect of immediate ART started at the time of very recent HIV infection, with ART + vaccine and vorinostat on measures of the HIV reservoir.

The kick and kill approach used in this study
• the “kick” was ten doses of 400mg tablets of Vorinostat taken every three days
• the “kill” was two vaccinations; a “prime” with ChAdV63.consv. and a “boost” with MVA.HIVconsv.

What is the HIV reservoir and how did we measure it’s behaviour?

The figure shows a cartoon of what we think a latently infected cell and an active cell might look like. Both are normal CD4+ T-cells that have a section of HIV genetic material (red) inside their own DNA (blue).

Latently infected cells seem to function normally and do not look any different from cells that do not have HIV DNA inside them, so they are “invisible” to the immune system.

New virus particles are not released from these latently infected cells unless they become activated. If ART medicines are in the blood then even if the latently infected cell gets activated the medicines will block any new virus being released from the cell and so there is no rise in HIV viral load in the blood.

Vorinostat, the drug used in this trial, activates the latently infected cells to start producing virus proteins. This represents the “kick” of the cure strategy we test in the RIVER trial.

Any latently infected cell that is forced to express virus proteins is then no longer ignored by the immune system. The vaccination used in the RIVER trial encourages the immune system to recognise any activated reservoir cells and destroy them.

The latently infected cells, for people on ART with undetectable HIV viral loads, are very rare in the blood (probably less than 1 in every million CD4+ T-cells) and so the body can replace those cells that might be killed by this approach with new healthy cells very rapidly.

In RIVER these are the HIV reservoir measurements we made:
1. To measure the viral reservoir in this study we counted the number of CD4+ T-cells that look like a latently infected cell: this is the number of CD4+ T-cells that have detectable HIV DNA inside them for every million CD4+ T-cells in the blood sample (Total HIV DNA/million CD4+ T-cells). This is the main measure of HIV reservoir for the trial.
2. We also measured if we could stimulate the blood cells in a test tube, to see if virus particles would grow out from the blood cells (like the cell on the right-hand side above) (viral outgrowth assay, VOA).
3. We did very sensitive tests in research laboratories to see if we can find very low levels of virus particles (Ultra-sensitive viral load < 1 copy HIV RNA/ml).
4. And the same as (3) for virus proteins (p24 assay).
5. To check if the vaccine was working to increase the immune responses to HIV proteins we measured in the test tube how the CD4+ T-cells and CD8+ T-cells reacted to stimulation with virus proteins (HIV-specific immunity, ICS and VIA).
6. We checked if vorinostat worked how we expected it to by measuring cell gene activation (HDAC inhibition).
7. Finally, the other very important outcome that we looked at in RIVER is safety and how well tolerated the medicines and vaccine were. This is detailed in the Safety section below.

Study design:
We enrolled 60 study participants across [6] centres in London and Brighton. All study participants had confirmed recent HIV infection and all started on ART within a maximum of four weeks from their date of HIV diagnosis. Once their viral load was suppressed to < 50 copies HIV RNA/ml, participants were randomly allocated to one of two study groups, on a 1:1 basis; 30 in each arm.

the control group ART alone
the intervention group ART + vaccine + vorinostat.

The main measure of the trial – measurement (1) above – the total HIV DNA/million CD4+ T-cells was counted at weeks 16 and 18 after the random allocation into one of the two study groups.

Results in more detail:
83 participants were screened and in total 60 study participants were enrolled into the trial. All participants were men, the average age was 32 years, and average CD4+ T-cell count at randomisation was 708 cells/mm3.

No participant withdrew nor was lost from the study after randomisation. In the experience of the clinicians and investigators, this is outstanding.

All study participants stayed on ART throughout the trial and only three changed ART regimen after randomisation, for toxicity reasons. Self-reported non-adherence (missing any dose in the past seven days) was recorded at 6% of all visits across all participants, with no difference between the arms.

All 30 participants in the intervention arm received two vaccines as scheduled; 27 participants received all 10 doses of vorinostat as scheduled.

Main measure: Total HIV DNA/million CD4+ T-cells at weeks 16 and 18 after randomisation

At enrolment the average total HIV-DNA of all participants was 3.84 log10 copies/million CD4+ T-cells. This decreased to 3.14 at randomisation. Total HIV-DNA then decreased further by weeks 16/18. There was no significant difference between the two arms in terms of the total HIV DNA measures at weeks 16 & 18 (red compared with blue in the graph).

The figure shows the changes in measures of total HIV DNA where a dot represents the results of each individuals’ blood sample. The red dots are measures of total HIV DNA for people who were in the control arm of the trial, and blue dots are for those in the intervention arm. We compare the average level of HIV DNA between the red and the blue. We show that whilst there is a very large drop (I log is a very big drop in the measure of HIV reservoir), from around 4.00 at the beginning to 3.00 after almost a year), this drop was similar for both arms of the trial (the average for the red and blue dots are around the same level). There is a wide range of the levels of HIV DNA for each time point measured. We would like to try to explain this with more research laboratory tests from the stored blood samples, for example some people have very low levels of HIV DNA right from the start (nearly 2.00) and others start with very high levels (nearly 5.00). We would like to better understand why this is and what this might mean.

Did cell stimulation lead to virus production in a test-tube? The viral outgrowth assays (VOA)

There was no significant change in VOA test results between the study arms from randomisation to the final study visit at week 16: for both the control and intervention arms, virus could be detected on stimulation of CD4+ T-cells for 60% of individuals at randomisation and a similar 64% at week 16.
However, we saw a very high proportion of people (around 40%) where we could not grow virus from their cells in this assay, higher than we would anticipate for people on ART who started at later stage disease. This might show how effective ART is at limiting virus activity.

Did the two vaccinations improve the immune responses to HIV? HIV-specific T-cell responses:

Participants in the intervention arm showed significantly higher HIV-specific CD4+ T-cell responses than those participants who did not receive the vaccinations in the control arm.

Did the HIV-specific T-cell responses kill HIV test cells in a test-tube? CD8+ T-cell antiviral activity – viral inhibition:

To test if the vaccine had stimulated CD8+ T-cells to recognise and kill HIV-infected cells, CD8+ killer T-cells from the study participants were added into a test-tube that contained CD4+ T-cells expressing HIV. This test is called the viral inhibition assay (VIA). The measure of participants from the control arm inhibiting virus in this test decreased over time, suggesting that on ART the number and function of the HIV-specific killer CD8+ T-cells in the blood declined, whereas in the intervention arm there remained strong HIV inhibition in this test over time.

Did the vorinostat work how we expected it to – did it affect cell gene expression; HDAC inhibition?

For participants in the intervention arm of the trial, blood samples were taken before a dose of vorinostat and two hours after. Twenty-two patients in the intervention arm provided a total of 41 pre and post dose results. Averaged across all time-points, acetylation two hours post vorinostat had increased by a factor of 3.2 compared to pre vorinostat, with no difference between visits. This means that the vorinostat worked on histone deacetylation as we would have expected and to a level similar to previous reports using this dose of the drug.

Note: Results for the ultra-sensitive viral load assay (point 3 above) and the p24 assay (point 4 above) are not yet completed.


Safety reporting for studies of new agents is very strict and requires full reporting of any symptoms whether they are thought to be related to the study or the study intervention or not. The events are graded for severity where grade 4 is a very serious event and grades 1 and 2 are minor symptoms such as discomfort, rash, and headache.

There were no deaths, pregnancies in a partner, cancer, or pre-specified vaccine related adverse events. Only one serious adverse event was reported post-randomisation, which was not considered to be related to the study or drug intervention.

Clinical adverse events were reported for 97% of participants in the intervention and 73% in the control arm. The number of adverse events per individual was higher in the intervention arm (median 3 vs. 1 event per person). However, the maximum grade was higher in the control arm, with six participants presenting with a grade 3 event (1 event for each of the following: hepatitis; influenza; Herpes proctitis; shingles; wrist injury; back pain) vs. 1 individual in intervention (back pain).

A clinical adverse event possibly, probably or definitely related to the vaccines was reported for 53% of intervention participants. However, most events were mild, only three patients had a grade 2 event (tiredness, pain at injection site, rash), and none a grade 3 or 4 clinical event. 93% of vaccinated participants reported any local or systemic solicited vaccine event, with maximum grade 1 in 37%, grade 2 in 43%, and grade 3 in 13% (1 pain/chills post MVA, 1 pain/headache post MVA vaccine, 1 itching post ChAd vaccine, 1 chills/tiredness post ChAd vaccine & tiredness post MVA vaccine; all reported on the patient diary).

A clinical adverse event related to vorinostat was reported for 76% participants who started vorinostat. Again, most events were mild, six patients had a grade 2 event (1 diarrhoea, 2 dry mouth, 3 tiredness, 1 night sweats, 1 impaired glucose tolerance), and none a grade 3 or 4 clinical event.
Laboratory events (those based on flags raised by blood analysis in the lab) were reported in 75% of all participants, with no difference between the arms (p=0.58). 3% of participants reported a grade 4 event (1 intervention: raised liver function test; 1 control: raised creatine kinase (CK), and another 3% a grade 3 event (1 intervention: raised CK; 1 control: low glucose).

Further information

If you have any questions about the RIVER trial, please speak to your doctor or research nurse. RIVER trial is registered with the clinical (#NCT02336074) and ISRCTN (#ISRCTN 83717528).

The RIVER trial was sponsored by Imperial College London. It was funded by MRC, MSD and GSK. For more information visit

RIVER trial findings presented at AIDS 2018


The results of the RIVER trial, coordinated by the CHERUB consortium, will be presented at the 22nd International AIDS Conference which will be held in Amsterdam on 23rd – 27th July 2018.

The RIVER presentation will take place on Tuesday, 24th July 2018.

CHERUB HIV Garden RHS Chelsea – May 2018

Artist Impression

Great news! The ‘CHERUB HIV Garden: A life without walls’ will be presented at the 2018 RHS Chelsea Flower Show. The garden is focused on the journey a young person living with HIV takes and explores issues around stigma and openness. Do come along and see us there from May 22-26th 2018.

Slides from the HEATHER participant meeting – Sep 2017

We recently held a patient feedback meeting at the Imperial College Medical School in London. Please see below slides from the meeting.

Welcome and HEATHER Summary

Patient survey and attitudes to cure research

Where does my sample go?

Breaking down the camouflage

Gut instinct