Laird Harrison

September 10, 2012

September 10, 2012 (San Francisco, California) — At least 17 patients taking natalizumab have experienced serious herpes simplex or varicella zoster infections since November 2004, researchers reported here at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.

Most of the patients underwent long hospitalizations and received systemic antiviral therapy; 2 died.

The risk for central nervous system (CNS) infection is already included in the labeling of natalizumab, but this research confirms the danger, first author Andrew J. Fine, PharmD, a pharmacists at the US Food and Drug Administration (FDA), told Medscape Medical News. "This shows that this problem is occurring," he added.

Natalizumab, a recombinant monoclonal antibody used in the treatment of multiple sclerosis and Crohn's disease, binds to the alpha-4 subunit of the alpha-4 beta-1 and alpha-4 beta-7 integrins expressed on all leukocytes except neutrophils.

Natalizumab reduces the adhesion of leukocytes to the surface of endothelial cells in the blood–brain barrier. This hinders their passage into the CNS, which reduces the intensity of the ongoing inflammatory reactions that cause clinical symptoms.

At the same time, in patients with multiple sclerosis, natalizumab decreases the cerebrospinal fluid ratio of CD4+ to CD8+ but has little effect on the ratio of CD4+ to CD8+ in the peripheral blood.

This weakens immune defenses in the CNS in general, and in particular raises the risk for multifocal leukoencephalopathy caused by the John Cunningham polyomavirus, Dr. Fine explained.

The drug also interferes with the passage of CD8+ T cells into the brain, he said. Preclinical studies suggest that CD8+ T cells weaken the viral reactivation in peripheral ganglia and protect against overwhelming CNS infections.

To determine whether the drug makes patients more vulnerable to CNS infections, Dr. Fine and his colleagues searched the FDA Adverse Event Reporting System from November 2004 to June 2012 for all serious natalizumab postmarket adverse-event reports.

They found 17 reports of confirmed herpes virus infections, only 5 of which had been reported in the literature.

Of these 17 cases, 10 occurred in the United States. Fourteen were in female patients. Nine were reported since 2011.

Nine patients suffered encephalitis, which was the most common clinical symptom, followed by meningitis, which affected 6 patients.

All but 1 patient was hospitalized. Four were admitted to the intensive care unit. Two patients underwent blood transfusions to remove the natalizumab rapidly from their systems. Two patients died and 2 had neurologic sequelae.

Natalizumab was discontinued in 15 patients and continued in 1; for the remaining patient, disposition ws not known.

Dr. Fine said it is important for physicians to be aware of the risk for this type of infection, not only with natalizumab but also with other monoclonal immunosuppressant drugs.

"These are latent viruses that are fairly common," he said.

The finding came as a surprise to Stefan Schwartz, MD, a senior hematologist at Charité University in Berlin, Germany. "I didn't know about these complications," he told Medscape Medical News.

There is no national registry for these types of postmarket adverse events in Germany, he said. Although the viruses are common, he recommends that all patients taking natalizumab be tested for them.

Dr. Schwartz and Dr. Fine have disclosed no relevant financial relationships.

52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract T-342. Presented September 9, 2012.