ACTG Presents Study at CROI Elucidating Mechanism of CMV on Aging-Related Pathways in HIV

Mar 08, 2024

LOS ANGELES, March 04, 2024 (GLOBE NEWSWIRE) — ACTG, a global clinical trials network focused on HIV and other infectious diseases, today presented the poster “Suppressing Asymptomatic CMV with Letermovir Reshapes Cardiometabolic Proteome in Treated HIV” at the Conference on Retroviruses and Opportunistic Infections (CROI 2024), in Denver, Colorado. Today’s presentation from study A5383 is the first to demonstrate that a specific inhibitor of cytomegalovirus (CMV) is safe and broadly impacts immunologic and cardiometabolic biomarkers in people living with HIV, which may explain the association between CMV and aging-related HIV co-morbidities.

CMV is a chronic and usually asymptomatic virus carried by 60 percent of adults in the general population and more than 95 percent of people living with HIV. Prior to the availability of effective antiretroviral therapy (ART) for HIV, CMV caused life-threatening infections in the eyes, brain, and gut in people with compromised immune systems due to advanced HIV. While the immune system recovery resulting from ART has rendered this type of CMV organ disease rare, CMV can still affect immune responses, including inflammation, even when it is not causing obvious symptoms.

“Investigators have found associations between CMV and heart disease, cancer, and other aging-related complications among people living with HIV,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “Until now, however, we were unable to prove that CMV is associated with these diseases. A5383 was successful at clarifying some of the underlying mechanisms, bringing us one step closer to developing approaches to support healthy aging over the lifespan in people living with HIV.”

A5383 is a phase 2, randomized, open-label, multicenter trial assessing the impact of treating people living with HIV who are virally suppressed on ART and are CMV seropositive without detectable virus in blood plasma (which means that they test positive for exposure to CMV but do not have symptoms) with letermovir, a CMV terminase inhibitor. Letermovir is CMV-specific and has no direct antiviral activity against other herpesviruses, enabling researchers to isolate the effect of CMV on the immune system. Participants in A5383 were randomized to either receive letermovir daily or no treatment for 48 weeks. A planned futility analysis (conducted to assess whether there is a low probability of the trial achieving its primary objective).after the first 39 participants completed eight weeks of therapy (N=18) or no treatment (N=21) found that instead of decreasing, the primary inflammatory endpoint (soluble tumor necrosis factor receptor 2, or sTNFR2) increased unexpectedly in the letermovir arm and the study was stopped early.

To explain these findings, the team hypothesized that CMV may suppress pathways of inflammation through its immunoregulatory viral IL-10 protein, which led them to conduct a series of follow-up investigations to characterize the effects of letermovir on various inflammatory and cardiometabolic pathways in the blood. As expected, letermovir decreased IL-10 receptor signaling, which may explain the unexpected increase in sTNFR2 (essentially it took the “foot off the brakes” of the TNF pathway).

Researchers found that letermovir reduced many important inflammatory pathways, including IL-1b and IL-6 receptors, which have both been causally linked to heart disease and cancer in other studies. Letermovir also improved several markers associated with atherosclerosis and endothelial dysfunction, suggesting a potential cardiovascular benefit. Metabolic pathways associated with insulin resistance also appeared to improve with letermovir. In addition, of five plasma biomarkers that were previously causally linked to heart disease in people living with HIV, three were suppressed significantly by letermovir.

“While it is too soon to say whether letermovir or another anti-CMV therapy will reduce the actual risk of heart attacks, cancer, and diabetes in people living with HIV, these are exciting new data that support this therapeutic concept, which we look forward to testing in future studies,” said Protocol Chair Peter Hunt, M.D., University of California at San Francisco. “It is particularly important because we don’t yet have any treatments that are able to reduce all of these aging-related diseases in people living with HIV.”

A5383 is led by Dr. Hunt and Sara Gianella, M.D., University of California San Diego (Co-Chair). ACTG is led by Dr. Currier and Joseph J. Eron, M.D., University of North Carolina (ACTG Vice-Chair). It is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (which also funds ACTG) under award numbers UM1 AI068636, UM1 AI107716, and UM1 AI068634. Study drugs are supplied by Merck & Co., Inc., Rahway, N.J., USA.

About ACTG
ACTG is the world’s largest and longest running clinical trials network focused on HIV and other infectious diseases and the people living with them. It is funded by NIAID and collaborating NIH Institutes. Founded in 1987, ACTG conducts research to improve the management of HIV and its comorbidities; develop a cure for HIV; and innovate treatments for tuberculosis, hepatitis B, and emerging infectious diseases. It comprises thousands of dedicated researchers, staff, and community members who are pursuing research into novel treatments and cures for infectious diseases at 65 locations across four continents, with the ultimate goal of advancing science that meaningfully impacts the lives of the people we serve.

Disclaimer: This content is solely the responsibility of ACTG and does not necessarily represent the official views of the NIH.

Media Contact:
Rachel Reiss, ACTG