CMV antiviral may reduce inflammation and improve immune function in people with HIV

Letermovir, an antiviral drug for cytomegalovirus (CMV), was associated with reduced inflammation, improved CD4/CD8 T-cell ratios and better physical function for people with HIV on effective antiretroviral treatment, according to a study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco.

Based on these findings, letermovir “is probably the most exciting intervention that has been done in people with HIV for inflammation and ageing over the last 20 years,” said lead researcher Dr Sara Gianelle Weibel of the University of California San Diego.

While antiretroviral therapy (ART) can suppress HIV replication indefinitely, people living with HIV are still prone to chronic inflammation that can contribute to co-morbidities such as cardiovascular disease and age-related effects such as frailty. CMV co-infection has been linked to increased risk of frailty and other detrimental effects of ageing in people with HIV.

A member of the herpesvirus family, CMV is transmitted via bodily fluids, including saliva and urine, during sex and from mother to child. Studies suggest that around a third of children, half of middle-aged adults and up to 90% of elderly people in the United States have had CMV, with even higher rates in low- and middle-income countries.

CMV is usually asymptomatic in people with a healthy immune system, but reactivation of the virus can cause severe illness in those with advanced immune suppression. Before the advent of effective antiretroviral treatment, people with AIDS were susceptible to CMV colitis (gastrointestinal illness), pneumonitis (lung inflammation), encephalitis (brain inflammation) and retinitis (retinal inflammation) that could lead to blindness.

Asymptomatic CMV infection is usually not treated, but letermovir (Prevymis) is used to prevent illness in CMV-positive people undergoing stem cell transplants, which involve immunosuppressive therapy. It is also used for CMV-negative recipients of a kidney transplant from a CMV-positive donor. Medications for treating CMV illness include ganciclovir, valganciclovir, foscarnet and cidofovir.

Reduced inflammation

Gianella Weibel and colleagues conducted the ACTG A5383 trial to evaluate whether letermovir would affect immunological and functional ageing-related outcomes among people with HIV who tested positive for CMV and were on suppressive ART.

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Study participants were randomly assigned to receive letermovir along with their antiretrovirals or ART alone for 48 weeks. The study initially aimed to enrol 180 people, with a planned futility analysis when the first 40 participants reached week 8.

This early analysis included 39 participants. About three-quarters were men, half were White, nearly 40% were Black and the median age was approximately 58 years. The median CD4 T-cell count was approximately 385, and more than 40% had a count below 350.

This analysis showed that people in the letermovir group had an unexpected increase in soluble tumour necrosis factor receptor 2 (sTNFR2) – a biomarker associated with inflammatory diseases – at week 8. Assuming that this early increase would predict poor longer-term outcomes, the trial was stopped early.

The researchers continued to follow participants through 48 weeks, however, and observed a sustained reduction in interleukin 10 (IL-10) receptor activity in the letermovir arm. There were also declines in several proteins associated with cardiovascular disease and cancer.

Further follow-up showed that after the temporary rise, sTNFR2 levels declined significantly between week 8 and week 48 in the letermovir group. Similar patterns were observed for the pro-inflammatory cytokine IL-6 and the inflammation biomarkers C-reactive protein and D-dimer. Letermovir also led to an early and sustained reduction in IL-1-beta, another pro-inflammatory cytokine linked to cardiovascular disease and cancer mortality.

As a possible explanation for these findings, Gianella Weibel noted that CMV produces a viral version of IL-10 that’s similar to the human anti-inflammatory cytokine IL-10, which helps the virus hide from the immune system. “We believe when we started letermovir and blocked CMV replication, we also blocked viral IL-10, which was like taking the foot off the brake of the immune system,” she said.

As expected, letermovir suppressed mucosal CMV shedding in semen, throat, rectal and cervical samples. During treatment, there were only two samples (both semen) with detectable CMV DNA in the letermovir group. CMV shedding remained suppressed for up to 12 weeks after stopping the drug. CMV DNA was undetectable in all plasma samples tested during the study.

CMV-specific antibody titres declined during letermovir treatment but started rising again after the drug was stopped, suggesting that the immune system was starting to sense the virus in the early post-treatment period even though CMV shedding remained suppressed, Gianella Weibel said.

Improved immune function

Another study presented at the conference showed how CMV infection affects immune function. Dr Raynell Lang of the University of Calgary and colleagues compared immunological outcomes among more than 2500 people starting antiretroviral treatment; 91% tested positive for CMV. Those with a low CD4 count or low CD4/CD8 ratio (an indicator of better immune function) at baseline were excluded from the analysis.

Over 10 years of follow-up, CMV-positive and CMV-negative people were equally likely to reach a CD4 count of 500 or more (84% vs 85%, respectively). However, the CMV-positive group was less likely to achieve a normal CD4/CD8 ratio of 1 or higher (53% vs 72%). After two years of viral suppression, the median CD4 count and CD4/CD8 ratio were consistently higher in the CMV-negative group.

“We identified a high seroprevalence of CMV among people with HIV which was associated with a reduced CD4+/CD8+ ratio normalisation, suggesting CMV seropositivity is associated with persistent immune activation and inflammation among people with people with HIV who maintain HIV viral suppression on ART,” the study authors concluded.

In Gianella Weibel’s trial, people in the letermovir group experienced a significantly greater increase in their CD4 count, which was especially pronounced – a median gain of 93 cells – for those with a count below 350 at baseline. The letermovir group also saw a larger increase in the CD4/CD8 ratio, particularly among women.

What’s more, physical function improved in the letermovir group at 48 weeks, as indicated by a timed repeat chair-rise test, which correlated with an increased CD4/CD8 ratio. The study abstract noted that there was also a trend toward improvement in other functional outcomes such as grip strength and walking speed in this group.

Letermovir was generally safe and well tolerated, though some participants experienced diarrhoea and headache. “There was no evidence of serious safety concerns related letermovir,” Gianella Weibel reported.

“Letermovir initially increased some inflammatory markers but ultimately resulted in sustained reductions in inflammation, improved CD4/CD8 ratios and enhanced physical function/leg strength in people with HIV with CMV on suppressive ART,” the researchers concluded. “These findings suggest that suppression of asymptomatic CMV with a CMV-specific inhibitor may improve ageing-related outcomes.”

Gianella Weibel said that, in retrospect, it was probably a mistake to stop the trial early, but hopefully these results will inform and support a larger study.

Routinely offering letermovir for treatment of asymptomatic CMV in people with HIV is not feasible due to the drug’s high cost. Other CMV medications, such as valganciclovir, are less expensive but have side effects that make them unsuitable for long-term treatment. Letermovir “has a much better safety profile, so if we can bring the cost down, I think letermovir will be a much better candidate,” she said.

Gianella Weibel described one study participant, a long-time immunological non-responder with a CD4 count around 200, who saw her count rise to 800 for the first time while taking letermovir. “She was so sad, when the study was interrupted and she had to go off letermovir, that her CD4s dropped down,” Gianella Weibel recalled. Regarding the cost, she suggested that we might not have to treat everyone with CMV but might be able to pick those who would see the most advantage, such as women with a low CD4 count.