Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.
PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.
Asymptomatic Reactivation of the JC Virus Is Observed
Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.
At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.
Thorough Monitoring Is Recommended
“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.
“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.
“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.
—Rebecca K. Abma