RIVER Study: Kick & Kill Vaccine Strategy

Kick and kill strategy study yields disappointing results
by Jeannie Wraight

Latent HIV resides in cells in blood and tissue which we collectively call the HIV reservoir. The virus lays dormant in these cells, which can live for years, unlike most HIV- infected cells which die in a few months. Antiretroviral therapy destroys HIV in the blood but is unable to locate reservoir cells as these cells do not express viral proteins on their surfaces, making them “invisible” to ART and to the immune system. When ART is discontinued, virus from the reservoirs can awaken and begin replicating. With this eventuality, it’s hypothesized that destroying reservoirs could effectively eradicate HIV from the body.

Researchers believe that even if we cannot completely eliminate viral reservoirs, we may be able to achieve a functional cure by reducing the size of reservoirs. Doing so may allow for years, even decades, of treatment-free remission. Thus far, much of the efforts to do so have been centered on the kick and kill strategy, learning where the latent (resting) HIV hides, how big the reservoir might be, and how we identify, wake up and kill latent HIV.

With kick and kill, one or more drugs/vaccines would be used to prime the immune system, teaching it to recognize and destroy HIV. A separate drug would “wake” the virus from its resting or latent state and produce HIV viral proteins on their outer surface, enabling the immune system and ART to destroy the infected, once-latent, cells.
Highly anticipated results from the RIVER study provided more questions than answers in the first randomized clinical trial studying the kick and kill strategy. Researchers hoped to see a significant decrease in the amount of HIV in viral reservoirs. However, reservoir levels from those receiving the three-drug regimen in addition to ART were the same as those on ART alone.

The RIVER study recruited sixty male participants who had newly acquired HIV and who began an integrase-based regimen soon after diagnosis. Of the sixty, thirty participants then began a regimen of two therapeutic vaccines and vorinostat—a latency reversing agent (and cancer-fighting drug)—along with their ART regimen. The study ran from 2015 to 2017.

Initial data in April demonstrated that only half of the men who had received the full drug regimen had experienced a decrease in reservoir size. During the 2018 International AIDS Conference this past July, researchers additionally reported all of the separate components of the regimen functioned as expected, despite not achieving a drop in the size of the viral reservoir.

In the RIVER study, two therapeutic vaccines, hAdV63.HIVconsv and MVA.HIVconsv, were used to prepare the immune system. These vaccines were shown to be effective in producing immune responses in participants. Vorinostat was utilized as a latency-reversing agent to wake the latent HIV.

Of note, the RIVER study investigators spoke of the altruistic dedication on the part of the study participants, with all sixty participants completing the study with a 100-percent adherence to all study drugs and scheduled appointments. In many HIV-related studies, recruiting the full targeted number of participants, as well as ensuring a high level of adherence to study visits and medications, has been an ongoing problem for over a decade and a half. It’s heartwarming to see the dedication exhibited in the RIVER study and bolsters hope that cure studies will receive the commitment that they need to succeed.

The failure of the regimen used in the RIVER study doesn’t necessarily mean that the kick and kill theory is flawed. More studies are needed using different compounds to determine whether kick and kill is a viable course. Researchers are considering various options for a follow-up study. These include adding additional boosts of the vaccines and swapping out vorinostat for a more potent latency reversing agent. Vorinostat was the best option in 2014, when the study was designed; however, newer, more effective latency-reversing agents have since been researched. Another option suggested by the study investigators could be to utilize the next generation of the same vaccines, which are currently being studied.

With much of the cure/remission efforts directed towards the kick and kill strategy, the study of many other potential strategies and drugs have had difficulty gaining financial support and attention. Other possibilities such as gene therapies, monoclonal antibodies, therapeutic vaccines and novel classes of drugs such as APOBEC3G Inhibitors, are competing for sparse funding. One potential therapeutic that may also double as a cure component, FH5051, is a first in class translation inhibitor targeting the DDX3 RNA Helicase, a human host factor that is fundamental in HIV replication. FH5051 and the Netherlands company who created the compound, First Health Pharmaceuticals, have a unique story which will be highlighted in next month’s column.

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.