Introduction

In groundbreaking findings presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco, researchers have revealed that letermovir, an antiviral drug used for cytomegalovirus (CMV), may significantly reduce inflammation and enhance immune function among individuals living with HIV who are already on effective antiretroviral treatment.

Exciting Intervention

Lead investigator Dr. Sara Gianella Weibel from the University of California San Diego expressed that letermovir "is probably the most exciting intervention that has been done in people with HIV for inflammation and aging over the last 20 years." With antiretroviral therapy (ART) ensuring long-term suppression of HIV, chronic inflammation continues to plague many living with the virus, increasing the risk of conditions like cardiovascular disease and age-related decline.

Understanding CMV

CMV, part of the herpesvirus family, is commonly transmitted through bodily fluids. Interestingly, it affects a substantial portion of the population; studies show that about a third of children, half of middle-aged adults, and up to a staggering 90% of older adults in the United States have had CMV exposure. While typically asymptomatic in healthy individuals, reactivation of CMV can lead to severe complications, particularly in those with compromised immune systems, such as individuals with untreated AIDS.

Current CMV Therapies

Current therapeutic options for CMV include ganciclovir and foscarnet, but letermovir (marketed as Prevymis) is used primarily in patients undergoing stem cell or kidney transplants to prevent CMV-related illness.

Significant Findings from the ACTG A5383 Trial

The ACTG A5383 trial aimed to assess the impact of letermovir on immunological and functional aging outcomes in HIV-positive individuals with CMV. Participants were divided into two groups: one receiving letermovir alongside ART, and the other receiving ART alone.

Initially planned to involve 180 participants, the trial was halted early after an interim analysis revealed an unexpected increase in the soluble tumor necrosis factor receptor 2 (sTNFR2) levels—an inflammatory marker—in the letermovir group. However, further follow-up to the 48-week mark disclosed a sustained decline in inflammatory markers like interleukin-10 (IL-10) and several proteins linked to cardiovascular diseases.

As Dr. Gianella Weibel explained, blocking CMV replication with letermovir seems to help the immune system regain function by effectively "removing the foot off the brake" put on by CMV’s similar version of the anti-inflammatory IL-10.

Improvements Noted

Intriguingly, the study noted that, despite the initial spike in inflammatory markers, participants treated with letermovir exhibited a marked improvement in their CD4 T-cell count and CD4/CD8 ratio—crucial indicators of immune health—as well as enhanced physical function.

The Connection Between CMV and Immune Function

Another study presented at CROI highlighted the intricacies of how CMV infection affects immune responses in HIV-positive individuals. Although 91% of those studied tested positive for CMV, findings showed that people without CMV had more favorable outcomes regarding CD4 count normalization compared to CMV-positive individuals, indicating persistent immune activation and inflammation.

In Gianella Weibel's trial, the increase in CD4 counts was particularly notable for participants with counts below 350 initially, with participants in the letermovir group showing improved physical test results correlating with better immune function.

Safety Profile

Despite some reports of mild side effects like headache and diarrhea, letermovir was deemed generally safe and well-tolerated.

Conclusion: Hope on the Horizon

The results from these studies suggest that letermovir's ability to suppress asymptomatic CMV infections may yield broader benefits, particularly in improving aging-related outcomes for those living with HIV. Dr. Gianella Weibel reflected on the trial's early termination, noting a missed opportunity for deeper insights, but she remains optimistic that these findings pave the way for larger-scale studies.

As research continues to uncover the potential of this antiviral medication, the future looks promising for improving the health and longevity of individuals living with HIV. Stay tuned for more updates as science marches forward!