Checking emails during a meeting, cleaning the house while cooking dinner. We know that multitasking — doing multiple things at the same time — means that none of the tasks are completed to their fullest potential. The same can be said for our immune system, which is why infection with cytomegalovirus (CMV) could be a significant burden on the wellbeing of people who are living with HIV.
CTN Postdoctoral Fellow Dr. Léna Royston is launching CTNPT 047, a study to test whether letermovir, a new anti-CMV drug, enables the body to reverse the negative effects of the virus. The study is one of only two in the world using this drug in people living with HIV. The study aims to understand how CMV can increase inflammation and cause health issues in people living with HIV.
CMV is extremely common around the world, and even more so in people living with HIV. This immune juggling act can be difficult for the body to maintain, explained Dr. Royston.
“The immune system can control CMV very well on its own, but when HIV is present, it can be very tiring for the immune system,” she explained. “These two sources of inflammation lower the capacity of the immune system to respond to other pathogens, and even vaccines.”
People living with HIV often have increased inflammation throughout the body. This is caused by damage to the cells that line the intestines, which allows bacteria to leak into the bloodstream and cause inflammation, called bacterial translocation. This inflammation is thought to be the main cause of the increased rates of comorbidities, like heart disease, hypertension, and psychiatric disorders.
This inflammation persists even when HIV is well controlled by antiretrovirals (ART), which suggests that CMV is a main culprit for this continued inflammation and health risk. Anti-CMV drugs like letermovir may help decrease this harmful immune activation.
“Letermovir was approved in 2017 for use in transplant patients,” said Dr. Royston. “The drug works against a protein specific to CMV and nothing else, which is why we think it has so few side effects.”
Previous anti-CMV drugs had too many side effects to be safely tested in people living with HIV, making CTNPT 047 an exciting new frontier in understanding inflammation and co-morbidities related to HIV.
Can letermovir help the gut heal?
Dr. Royston and her team, supervised by Dr. Jean-Pierre Routy, are aiming to enroll 60 participants in Montréal. All participants will continue to take their ART regimen as prescribed; 40 will receive a daily dose of letermovir for 14 weeks, and 20 will take ART only.
Including the screening visit, there will be seven site visits over the course of the study where participants will have blood samples taken. The primary focus of the study will be to compare the levels of lipopolysaccharides (LPS) in the blood between the two study groups.
“LPS are fragments of the outer membrane of the bacteria,” explained Dr. Royston. “If you have a lot of microbes that have leaked out of the gut, we will find LPS in your blood. It’s an indicator of bacteria leaking into the blood.”
By reducing the effect of CMV with letermovir and allowing the gut to heal, Dr. Royston and her team expect to see lower levels of LPS than in participants on ART only.
The team is also looking for other markers of inflammation, as well as direct evidence of CMV on the immune system.
“Finding CMV in the blood can be very difficult, so we are also looking at whether the immune system is less reactive to CMV at the end of the treatment,” she said. “In addition, we are examining markers on the immune cells that can tell us if they are tired; we have a theory that these will be lower after the treatment.”
Participants in the study will also be asked if they would like to participate in a sub-study where they will undergo colonoscopies and colon biopsies performed in two separate visits at the beginning and end of the study.
“With this sub-study, we are looking at the direct effect of CMV on the cells of the gut and can do more precise analyses, before and after letermovir,” Dr. Royston explained. “This is a sub-study because not everyone will agree to the procedure, but in our previous studies, we found that many people agree to a colonoscopy because it is included as a part of their regular care and prevention.
Beyond letermovir: A major step in the fight against CMV
When Dr. Royston has finished the study and her CTN fellowship, she will return home to Switzerland to resume her practice as an infectious disease physician. But she doesn’t expect that she will be prescribing letermovir to very many of her clients, even if it is found to be effective against CMV.
“With the current cost of the drug, it’s not feasible to give it to everyone right now,” she explained. “The goal of our study is to understand CMV and how it affects inflammation and the gut.”
Not only is the drug expensive, it must be taken consistently in order to prevent CMV from rebounding.
“CMV has a lifelong latent state, meaning that it can remain hidden without any active replication,” she said. “Like ART and HIV, letermovir doesn’t eradicate CMV, but the virus won’t be able to replicate and infect other cells.”
Dr. Royston says that, if effective, the drug may be prescribed for people who need it most — those who are at the highest risk of inflammation and non-AIDS comorbidities. This targeted application of letermovir could be tested in larger studies once the results of CTNPT 047 are available.
But the impact of the study goes beyond the drug itself. By understanding the mechanism behind how CMV negatively impacts the gut and increases inflammation, Dr. Royston’s pilot study could open doors to the development of new techniques and drugs to combat CMV, and be a major step towards reducing health risks in people living with HIV.