Antiviral Therapy May Reduce Risk of Infection in AAV Patients, Clinical Study Suggests

Antiviral therapy prevents silent reactivation of cytomegalovirus (CMV) in ANCA-associated vasculitis (AAV) patients and improves patients’ immune responses, a proof-of-concept clinical study shows.

These results suggest that antiviral therapy may reduce the risk of infection in these patients.

The study, “Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis,” was published in the Journal of Infectious Diseases.

Infection is the leading cause of death in patients with AAV, which frequently have respiratory infections. Vaccines to prevent this type of infection have been shown to have little protective effect in these patients.

Previous studies have shown that AAV patients with an expansion of a disabled subset of T-cells — immune cells that recognize and fight pathogens — with signs of exhaustion and low immune response are at a higher risk of infections.

A significant expansion of these cells has been shown to occur exclusively in people previously infected with CMV, a common virus of the herpes family that, once in the body, remains there forever.

While CMV is usually harmless, it can be reactivated in periods when the immune system is weakened and cause serious problems in immunosuppressed or immunocompromised individuals.

Researchers in the United Kingdom have hypothesized that silent reactivation of CMV in ANCA-associated vasculitis patients may drive the expansion of these disabled T-cells associated with impaired immune response, and that antiviral therapy could help prevent this.

To investigate whether this was the case, they conducted a proof-of-concept, open-label, randomized clinical trial (NCT01633476) to evaluate the safety and effectiveness of Valtrex (valacyclovir), an antiviral therapy, in the suppression of CMV reactivation and whether this prevention could limit the expansion of disabled T-cells in AAV patients.

The study enrolled 38 CMV-positive AAV patients (25 men and 13 women) in stable remission. They were randomized to receive Valtrex four times a day for six months.

Blood and urine samples were collected monthly from participants to assess CMV reactivation, and the levels of disabled T-cells were measured at the beginning of the study and six months later.

After six months, 36 of the 38 patients were vaccinated with the pneumonia vaccine — which depends on the normal function of T-cells to exert its protective effects — and the response to the vaccine was evaluated four weeks later.

Valtrex treatment completely suppressed asymptomatic (silent) CMV reactivation, with treated patients having no CMV reactivation, and four untreated patients (21.1%) showing viral reactivation. After the end of treatment, three patients who had received Valtrex showed CMV reactivation.

After six months of treatment, patients showed a significant reduction (by 27%) in the levels of disabled T-cells, suggesting that prevention of CMV reactivation can effectively lower the levels of this subset of T-cells.

An additional analysis of the untreated patients showed that those with CMV reactivation had increased levels of disabled T-cells compared with those who had no reactivation, and that these levels were associated with the number of viral reactivation episodes.

Reduced levels of this subset of T-cells in treated patients was significantly associated with a better immune response to the vaccine, while episodes of CMV reactivation were linked to worse responses.

These findings suggest that prevention or suppression of CMV reactivation through antiviral therapy may have a relevant therapeutic benefit in CMV-positive AAV patients by improving their immune response.

The researchers emphasized the need for additional and larger studies to confirm the protective effect of CMV suppression in these patients and to assess CMV reactivation during the more active phase of AAV disease, when “it is anticipated that viral reactivation will be even higher … [as] patients are exposed to intensive immunosuppressive therapy and heightened systemic inflammation,” they wrote.