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Patients taking the oral multiple sclerosis drug fingolimod (Gilenya) in clinical trials were more likely to develop new varicella-zoster virus (VZV) infections than those in the placebo groups, researchers said, although the absolute risk was still relatively small.

Among patients enrolled in the drug's phase II and III trials, the rate of new zoster infections was 11 per 1,000 patient-years of drug exposure in those receiving fingolimod compared with six per 1,000 patient-years with placebo, according to Norman Putski, MD, of drugmaker Novartis Pharma in Basel, Switzerland, and colleagues.

The researchers, who also included several prominent academic scientists in the multiple sclerosis (MS) field, also examined postmarketing reports on fingolimod and calculated a rate of seven zoster infections per 1,000 patient-years, on the basis of some 54,000 patient-years of drug exposure, they reported online in .

Although these rates indicated that the risk to a given patient remained low, Putski and colleagues noted that adverse event reports indicated that it was higher than the average for all other disease-modifying MS treatments.

The issue of zoster risk has come to the fore with fingolimod because of two fatal cases. One involved a clinical trial participant who died of a disseminated primary VZV infection in 2008 after taking the drug for 10 months. The second was reported in April 2013 and involved a case of reactivated zoster infection in a patient who had taken fingolimod in a postmarketing observational study for 6 months following treatment with natalizumab (Tysabri) and a 3-month washout period.

Fingolimod's current label does not indicate a specific risk of zoster infection, but it does suggest VZV vaccination in patients without a history of chickenpox or previous vaccination and a 1-month waiting period after vaccination before starting the drug.

In an accompanying editorial, , of the University of Colorado School of Medicine in Aurora, said these and other data suggest a special relationship between fingolimod and VZV, such that the drug increases risk of infection more than with other MS drugs, yet this infection risk does not extend to all pathogens across the board.

He noted that fingolimod's method of action -- preventing migration of T lymphocytes out of the lymphatic system -- may increase susceptibility to infections that would be suppressed by pathogen-specific memory T cells, of which VZV is one. Tyler also raised the possibility, thus far unproven, that VZV relies on fingolimod's specific target (the sphingosine-1-phosphate receptor) for its life cycle.

Both Tyler and the study authors generally supported the label recommendations for VZV vaccination in patients without evidence of previous infection or vaccination, including antibody testing to confirm past exposure status. Putski and colleagues also suggested that patients at potential risk for shingles without a recent vaccination should be considered for it. The risk might be exacerbated with concomitant steroid therapy, they noted, such that antiviral prophylaxis may be an option for patients on fingolimod who need such treatment.

Tyler and Putski and colleagues also concurred that clinicians and patients should be vigilant about infection, so that treatment can begin early enough to keep cases from becoming severe. Fingolimod treatment can continue in most cases, but the drug should generally be stopped in complicated infections, they agreed.