RIVER - Research In Viral Eradication of HIV Reservoirs
Research type
Research Study
Full title
RIVER - Research In Viral Eradication of HIV Reservoirs, A two-arm (proof of concept) randomised phase II trial
IRAS ID
162784
Contact name
Sarah Fidler
Contact email
Sponsor organisation
Imperial College London
Eudract number
2014-001425-32
ISRCTN Number
ISRCTN83717528
Clinicaltrials.gov Identifier
Universal Trial Number (UTN), U1111-1163-2579
Duration of Study in the UK
6 years, 11 months, 31 days
Research summary
Research Summary
Current antiretroviral therapy (ART), while allowing HIV-infected persons to lead a healthy life with near-normal life expectancy, cannot cure HIV. If ART is ceased, HIV reappears from the viral reservoir. This HIV reservoir is hidden away inside long-lived dormant (sleeping) cells and is laid down in primary infection i.e. when a person first becomes HIV infected. These dormant cells can be woken up (the ‘kick’) by drugs like vorinostat, an HDAC inhibitor. This ‘kick’ then allows the immune system to ‘kill’ some of the reservoir cells. The aim of this study is to test whether the HIV reservoir can be reduced using a combination approach. In this study we are enrolling patients with primary infection and immediately starting a 4-drug combination ART in order to limit the size of the reservoir. Six months in, and provided the patients are eligible; they are randomised (like the toss of a coin) into one of 2 arms. In the first Arm, patients continue 4-drug ART. In the second Arm, patients continue 4-drug ART but in addition receive two different anti-HIV vaccines 8 weeks apart followed by 10 doses of vorinostat over 28 days. The vaccines should boost the immune system’s ability to kill reservoir cells activated by vorinostat. The strategy is known as ‘kick and kill’. We plan to enrol 52 people with 26 in each Arm. There are 15 study visits over 42 weeks with the same safety checks and blood draws. We believe the ‘kick and kill’ approach will significantly reduce the amount of HIV reservoir as measured by a blood draw at weeks 40 and 42 compared to using 4-drug ART alone. This is a ‘proof-of-principle’ study, it is really testing whether this strategy does actually reduce the size of the HIV reservoir and is safe.
Summary of 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
All participants were followed for a further 5 years to report on any further safety events, this follow up completed at the end of 2023 with no major safety concerns identified.
For more information visit: https://www.mrcctu.ucl.ac.uk/studies/all-studies/r/river/
REC name
South Central - Oxford A Research Ethics Committee
REC reference
14/SC/1372
Date of REC Opinion
23 Dec 2014
REC opinion
Further Information Favourable Opinion