This drug reduces inflammation and improves immune function in HIV patients

The antiviral drug letermovir (Prevymis), which targets cytomegalovirus (CMV), was associated with reduced inflammation, improved CD4 /CD8 T cell ratios, and better physical function in HIV patients who were receiving effective antiretroviral therapy, a study showed at the 2025 Conference on Retroviruses and Opportunistic Infections in San Francisco.

Based on the findings, letermovir “may be the most exciting intervention to target inflammation and aging in HIV patients in the last 20 years ,” said lead researcher Dr. Sarah Janela Weibel of the University of California, San Diego .

Although antiretroviral therapy (ART) can suppress HIV replication indefinitely, HIV-infected individuals remain susceptible to chronic inflammation, which may contribute to comorbidities such as cardiovascular disease and age-related effects such as frailty. CMV coinfection in HIV-infected individuals is associated with an increased risk of frailty and other adverse effects of aging.

Cytomegalovirus (CMV) belongs to the herpes virus family and is transmitted during sexual intercourse and between mothers and babies through body fluids such as saliva and urine. Studies have shown that about one-third of children, half of middle-aged adults, and up to 90% of the elderly in the United States have been infected with CMV, and the infection rate is even higher in low-income and middle-income countries.

CMV is usually asymptomatic in people with healthy immune systems, but reactivation of the virus in people with advanced immunosuppression can cause severe disease. Before the advent of effective antiretroviral therapy, AIDS patients were susceptible to CMV colitis, pneumonitis, encephalitis, and retinitis, which can cause blindness.

Asymptomatic CMV infection is not usually treated, but letermovir (Prevymis) is used to prevent disease in CMV-positive people who are undergoing stem cell transplants (which involve immunosuppressive therapy). It is also used in CMV-negative recipients of kidney transplants from CMV-positive donors. Drugs that treat CMV disease include ganciclovir, valganciclovir, foscarnet, and cidofovir.

Reduces inflammation

Janela Weibel and colleagues conducted the ACTG A5383 trial to evaluate whether letermovir affects immunological and functional aging-related outcomes in CMV-positive HIV patients who are receiving suppressive ART.

Study participants were randomly assigned to receive letermovir in combination with an antiretroviral drug or ART alone for 48 weeks. The study initially planned to enroll 180 people, with a planned futility analysis to be conducted 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 about 58. The median CD4 T-cell count was about 385, and more than 40% had counts below 350.

The analysis showed that people in the letermovir group had an unexpected increase in soluble tumor necrosis factor receptor 2 (sTNFR2), a biomarker associated with inflammatory disease, at week 8. The trial was stopped early on the assumption that this early increase would predict poor long-term outcomes.

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

Further follow-up showed that in the letermovir group, sTNFR2 levels decreased significantly between weeks 8 and 48. A similar pattern was observed for the proinflammatory cytokine IL-6 and the inflammatory biomarkers C-reactive protein and D-dimer. Letermovir also led to an early and sustained reduction in the proinflammatory cytokine IL-1β, which is associated with cardiovascular disease and cancer mortality.

As a possible explanation for these findings, Janela Weibel points out that CMV produces a viral version of the human anti-inflammatory cytokine IL-10, which helps the virus hide from the immune system. “We believe that when we started using letermovir and blocked CMV replication, we also blocked viral IL-10, which was like releasing the brakes on the immune system,” she says.

As expected, letermovir inhibited mucosal CMV shedding in semen, throat, rectal, and cervical specimens. During treatment, CMV DNA was detected in only two samples (both semen) in the letermovir group. After drug withdrawal, inhibition of CMV shedding persisted for up to 12 weeks. CMV DNA was undetectable in any plasma specimen tested during the study.

CMV-specific antibody titers declined during letermovir treatment but began to rise again after drug withdrawal, suggesting that even though CMV shedding remains suppressed, the immune system begins to sense the virus at an early stage after drug withdrawal, says Janela Weibel.

Improve immune function

Another study presented at the meeting showed how CMV infection affects immune function . Dr. Reinel Langer of the University of Calgary and colleagues compared the immunological outcomes of more than 2,500 people who started antiretroviral therapy; 91% of them tested positive for CMV. People with low CD4 counts or low CD4/CD8 ratios (indicators of better immune function) at baseline were excluded from the analysis.

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

“We found high CMV seroprevalence in HIV populations, which was associated with reduced normalization of the CD4+/CD8+ ratio, suggesting that CMV seropositivity is associated with persistent immune activation and inflammation in HIV populations maintaining HIV viral suppression on ART,” the study authors concluded.

In Janella Weibel’s trial, people in the letermovir group had a significant increase in CD4 counts, especially those with counts below 350 at baseline—a median increase of 93 cells. The increase in the CD4/CD8 ratio was also greater in the letermovir group, especially in women.

More importantly, the letermovir group had improved physical function at week 48, as measured by the timed repeated stand test, which correlated with an increase in the CD4/CD8 ratio. Other functional outcomes, such as grip strength and walking speed, also trended toward improvement in this group, the study abstract states.

Letermovir was generally safe and well tolerated, although some participants experienced diarrhea and headaches. “There was no evidence of serious safety issues with letermovir,” reports Janela Weibel.

The researchers concluded: “ Letermovir initially increased some inflammatory markers but ultimately resulted in sustained reductions in inflammation, improved CD4/CD8 ratios, and increased physical function/leg strength in HIV- and CMV-infected individuals receiving suppressive ART. These findings suggest that suppression of asymptomatic CMV with CMV-specific inhibitors may improve outcomes associated with aging.”

Janela Weber said that in hindsight, it may have been a mistake to terminate the trial early, but she hoped that the results would provide information and support for larger studies.

Routinely offering asymptomatic CMV treatment to HIV patients is not feasible because of the high cost of letermovir. Other CMV drugs, such as valganciclovir, are cheaper, but side effects make them unsuitable for long-term treatment. Letermovir “has a better safety profile, so if the cost could be reduced, I think letermovir would be a better option,” she said.

Janella Weibel described one study participant, a long-term immune nonresponder with a CD4 count of about 200, who first rose to 800 while taking letermovir. “When the study was interrupted and she had to stop letermovir, her CD4 count dropped,” she lamented. Regarding costs, she suggested that it might not be necessary to treat all people with CMV infection, but that it might be possible to select those who would benefit most, such as women with low CD4 counts.