Groundbreaking Study Findings

A groundbreaking study has unveiled that Letermovir, an antiviral medication primarily used to combat cytomegalovirus (CMV), may significantly reduce inflammation and improve immune function in individuals living with HIV who are undergoing effective antiretroviral treatment. These compelling findings were presented at the highly anticipated Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco.

Exciting Intervention!

Lead researcher Dr. Sara Gianella Weibel from the University of California San Diego described Letermovir as “probably the most exciting intervention that has been done in people with HIV for inflammation and aging over the last 20 years.” This marks a potential turning point in the fight against chronic inflammation, a common issue that plagues individuals living with HIV, and can lead to serious health complications including cardiovascular disease and age-related frailty.

Chronic Inflammation in HIV Patients

While antiretroviral therapy (ART) is effective in suppressing the HIV virus, many patients continue to face chronic inflammation due to various factors, including CMV co-infection. CMV, a member of the herpesvirus family, can have detrimental effects, particularly among HIV-positive individuals, by exacerbating the aging process and increasing susceptibility to frailty. Understanding more about CMV is crucial, as studies indicate that around 90% of older adults in the United States harbor the virus, often without any symptoms.

The ACTG A5383 Trial

Dr. Gianella Weibel and her team conducted the ACTG A5383 trial to observe whether Letermovir could positively affect inflammation-related immune responses and overall functionality in HIV-positive patients who also tested positive for CMV. Participants were randomly assigned to receive Letermovir combined with their antiretroviral regimen or ART alone over a span of 48 weeks.

Initial Findings and Biomarkers

Initial findings from a planned early analysis of the first 40 enrollees revealed an unexpected rise in soluble tumour necrosis factor receptor 2 (sTNFR2), a biomarker linked to inflammation. Despite the early concerns leading to the trial’s premature cessation, further data collected over 48 weeks demonstrated a remarkable sustained decline in multiple inflammatory markers, including interleukin 10 (IL-10) and pro-inflammatory cytokines associated with serious health risks such as cardiovascular ailments and cancer.

Effects on Immune Function

Particularly intriguing was the finding that blocking CMV replication with Letermovir may diminish the levels of a viral imitation of the human anti-inflammatory cytokine IL-10, ultimately 'taking the foot off the brake of the immune system,' as Dr. Gianella Weibel articulated. Letermovir also effectively suppressed CMV shedding in various bodily fluids, indicating its potential long-term benefits even after treatment cessation.

Related Research on CD4 Counts

In another related presentation at CROI 2025, Dr. Raynell Lang and her team analyzed over 2,500 people beginning ART, with 91% testing positive for CMV. They confirmed that while achieving a healthy CD4 count was similar between CMV-positive and negative individuals, normalization of the CD4/CD8 ratio—a crucial measure of immune resilience—was notably impaired in the CMV-positive group.

Improvements Observed in CD4 Cells and Physical Function

Within the context of the letermovir trial, participants experienced an impressive median increase of 93 CD4 cells over the duration of the study, especially among those starting with lower counts. Moreover, physical function improvements were observed, suggesting that as immune function enhances, so too does overall health and vitality.

Safety and Future Research

Importantly, Letermovir was generally safe, with only mild side effects reported, such as diarrhea and headaches. The researchers concluded that despite initial concerns about inflammation spikes, the overall outcome demonstrated sustained reductions in inflammatory markers and improvements in immune parameters and physical capabilities.

Concluding Thoughts

Reflecting on the early halting of the trial, Dr. Gianella Weibel stated that it might have been premature, leaving hope for future studies to confirm the promising findings. This compelling research points to the potential for Letermovir not just as an antiviral, but as a significant player in the management of aging-related challenges for individuals living with HIV.