Pause, Not Rewind
COVID-19 Has Slowed or Halted HIV Studies, But Research Must Continue
by Jeannie Wraight
or most of the U.S. and all but a few countries around the world, life as we know it has been severely altered by the novel coronavirus, SARS Cov-2. The U.S. is unlikely to return to any resemblance of normalcy until a vaccine is discovered, which will take a year at minimum. Both a vaccine and effective therapeutics against COVID-19 are now the main priorities in medical research. However, we must ensure that the search for HIV cure and remission strategies, as well as an effective HIV vaccine, are not forgotten.
Many HIV/AIDS nonprofit organizations in the U.S and abroad such as, Care and Take Care, a Dutch NGO, have raised concern about how the COVID-19 emergency has affected people living with HIV (PLWH), and is creating a stagnation in already dwindling HIV cure and vaccine research. This particularly in light of the recent discontinuation of HVTN 702 and the current interruptions in HIV vaccine studies due to the COVID-19 pandemic.
HVTN 702 was a multi-center preventative vaccine study of over 5,400 individuals throughout South Africa. An independent review board responsible for monitoring the interim data determined that the vaccine candidate is ineffective against HIV. HVTN 702 was based on the well-known RV144 study which found an earlier version of the vaccine used in HVTN 702 to have a 31% protection rate against HIV. In addition to this failed study, three separate large HIV vaccine studies are experiencing difficulties due to the COVID-19 pandemic.
HVTN 706/ HPX3002, also known as the Mosaic trial, has been temporarily halted. Its sister study, Imbukodo or HVTN 705/HPX2008, a large multi-centered study, is also temporarily suspended and will determine future actions based on individual sites and their current local circumstances. The AMP studies that are investigating broadly neutralizing antibodies to prevent HIV acquisition in parallel studies, HVTN 704/HPTN 081 and HVTN 705/HPTN 085, have decided to discontinue future infusions, opting to move forward only with the study participants who have already received treatment.
Conversely, as HIV vaccine studies are slowed, the search for an effective cure is progressing with DDX3 RNA Helicase Inhibitors and TLR7 agonists, the strategies of the Dutch company First Health Pharmaceuticals, to block and eradicate HIV/AIDS.
DDX3 RNA Helicase inhibitors (DDX3 inhibitors) are a class of drugs that target an enzyme called RNA Helicase which is responsible for many aspects of RNA metabolism. HIV, as other RNA viruses, hijack this enzyme to complete its replication cycle. DDX3 Inhibitors effectively interrupt this process, preventing viral reproduction. As DDX3 is a human protein, the virus is unable to mutate in order to avoid this class of drug. As a result, researchers believe that resistance to DDX3 Inhibitors does not occur as it can with other antiviral drugs. Long studies in cellular models strongly support this hypothesis.
TLR7 agonists belong to a class of drugs called Toll-like receptor (TLR) agonists that have been shown to activate HIV viral reactivation in CD4+T cells. TLR7 agonists will be used to awaken HIV-infected CD4 cells in viral reservoirs, and in combination with DDX3 inhibitors eliminate the awakened infected cells.
Before the crisis, three multicenter projects on HIV reservoir reduction were designed to take place in the Netherlands and South Africa. These projects will assess various strategies aimed at activating latent HIV in viral reservoirs and eradicating these cells through the use of latency reversal agents, antiretrovirals and the body’s immune response (shock and kill). Among these strategies, the DDX3 inhibitors and TLR7 agonists will be evaluated toward clinical development.
The projects are public/private research initiatives and the collaboration of Erasmus Medical Centre (EMC), Amsterdam University Medical Center (AUMC), Utrecht Medical Centre (UMC), ViiV Healthcare, HIV Vereniging (The Dutch Association of People Living with HIV), and First Health Pharmaceuticals.
The multi-center research projects ensure sharing of knowledge to advance research. Drug makers involved in this project will have access to advanced models to test the effects of drugs such as the DDX3 inhibitors on patients’ samples with high translational value for further clinical trials, and in turn will offer the possibility to research medical groups to access and test proprietary technology.
Previous attempts at this ‘shock and kill’ strategy through the use of other latency reversal agents such as HDACs inhibitors have not proven successful and were affected by the high toxicities of the compounds. However, RNA Helicase Inhibitors and TLR7 agonists act at different levels and may maintain certain characteristics that make these drugs more viable options for this cure strategy.
In addition to their known effect as inhibitors of viral replication, DDX3 inhibitors are able to induce selective cell death, as seen in cancer cells.
In these unsure and difficult times when the world is witnessing the spread and destruction of the novel coronavirus, all efforts must be directed towards effective therapeutics and a successful vaccine to treat and prevent this new pandemic. However, as we recently witnessed the success of the documented cure of a second HIV- positive person, we must also stay true to the path of research and development for an efficacious HIV vaccine and effective cure strategies for the 37.9 million people currently living with HIV.
Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.