Investigators report results of the first randomized clinical trial to test a novel strategy to wake up and kill dormant HIV hiding in reservoir cells.
Initial results from the first randomized clinical trial dedicated to evaluating an experimental “kick and kill” approach for eradicating dormant HIV hiding in the body have been reported by investigators at the International AIDS Society’s annual meeting held in Amsterdam, the Netherlands (AIDS 2018).
Although the trial, referred to as the RIVER study, did not find a difference in effect between those who received the “kick and kill” therapy and those who were given standard antiretroviral treatment (ART), the investigators stress that the “kick and kill” approach opens the door to exploring different therapy combinations to fight dormant HIV reservoirs and demonstrates the importance of looking outside of current therapeutic approaches in the quest for a cure.
The randomized phase 2 trial, led by investigators from the Imperial College of London, the University of Oxford, the Medical Research Council Clinical Trials Unit at University College London, and the University of Cambridge, assessed the “kick and kill” approach in a total of 60 men who had recently been diagnosed with HIV and who were virally suppressed on ART. The trial ran for 3 years, from 2015 to 2018, in London and Brighton.
Individuals on ART are able to achieve viral suppression, and have undetectable levels of HIV in their blood, by adhering to their therapy regimen. This also renders these individuals sexually noninfectious. However, viral suppression does not equate to a cure; if an individual stops taking ART, dormant HIV hiding in reservoirs can reactivate and cause active infection once more. This knowledge has led investigators to hypothesize that a potential cure for HIV may lie in killing the HIV hiding out in these reservoirs.
“For those who have access to it, ART brings amazing success in managing HIV, but people have to take it for most of their lives,” chief investigator Sarah Fidler, PhD, MBBS, FRCP, a professor at Imperial College of London, said in a recent statement. “We have to think about other, sustainable alternatives and a cure or at least some form of remission is a key goal.”
Enter the “kick and kill” strategy.
For the RIVER trial, investigators used 2 different therapies in addition to standard ART: vorinostat, a drug typically used for managing cancer, which would work to “wake up” reservoir cells (CD4 T cells) by forcing HIV out of its hiding place to face the immune system, and 2 vaccines—ChAdV63.HIVconsv and MVA.HIVconsv—which would work to help the immune system not only recognize HIV, but also eliminate it.
The goal of the trial was for those receiving the “kick and kill” treatment approach to experience a significant decrease in viral levels in the CD4 T cells. However, when the results first came out in April 2018, the investigators found that those who were given the “kick and kill” approach in addition to ART still had comparable levels of infected CD4 T cells compared with those who just received standard ART.
“In the RIVER study, we found that all the separate parts of the kick and kill approach worked as expected and were safe,” Dr. Fidler explained. “The vaccine worked on the immune system, the kick drug behaved as we expected it to, and the ART worked in suppressing viral load in the body, but the study has shown that this particular set of treatments together didn’t add up to a potential cure for HIV, based on what we’ve seen so far.”
Because of their findings, the investigators were unable to recommend that participants receive the “kick and kill” drugs in addition to ART; furthermore, evidence was not found to support that any of the study participants could safely stop taking ART.
“We need to think about why we didn’t see an effect,” co-principal investigator and scientific lead of the study John Frater, a professor at the University of Oxford, stressed. “The important thing to realize is that despite these disappointing results, it does not mean that the basis of the approach is wrong.” He added that the issue could have lied in the combination of the drugs used, that vorinostat may not have been potent enough to wake up as much of the virus as was needed for the immune system to recognize.
As such, providing more boosts of this vaccination together with a different “kick” drug may be explored in further research or evaluating the “next generation” of the vaccines used in the study that are now being assessed in other trials, could also be worth further exploration, according to the investigators.