Tysabri Screening Test May Be Unreliable
About
one-third of multiple sclerosis patients testing negative for
antibodies against the JC virus -- suggesting that natalizumab (Tysabri)
would be relatively safe -- were found to have active viremia,
researchers said.
The report, published in the June 6 issue of the New England Journal of Medicine,
raises the specter that patients with negative JC serology results
could be given natalizumab when they may actually be at high risk for
progressive multifocal leukoencephalopathy (PML), an often fatal type of
brain inflammation.
PML
is caused by JC virus becoming active in the brain. Natalizumab appears
to contribute to reactivation of latent JC virus infections. MS
patients with such infections face a PML risk while on natalizumab
ranging from about 0.01% to 0.1% depending on the presence of other risk
factors
Eugene
O. Major, PhD, of the National Institute of Neurological Disorders and
Stroke in Bethesda, Md., and colleagues reported having tested blood
samples from 49 patients for anti-JC virus antibodies and for JC virus
DNA.
In
26 of the patients, the samples were obtained immediately before
starting on natalizumab. Samples from the other 23 were obtained after
at least 2 years of periodic natalizumab infusions.
Ten
patients in the first group were found to have JC viral DNA in their
blood, with four lacking a positive result in anti-JC virus antibody
testing. (Seronegativity was defined as antibody titers of less than
2,560 units.)
In
the group of 23 patients tested after 2 years of natalizumab treatment,
seven were found to be viremic and two were seronegative, the
researchers reported.
Overall, they indicated, six of 17 patients (35%) showing JC viremia were seronegative with the antibody test.
Fisher's
exact test indicated that the rate of viremia in the 49 patients was
significantly greater than in 18 healthy volunteers also undergoing
viral DNA testing (P=0.003), in whom none showed evidence of the virus in blood.
"The
relatively high percentage of patients who had viremia and were
seronegative appears to be greater than the false negative rate
identified previously," Major and colleagues wrote.
Currently,
the FDA and natalizumab's label recommend JC virus antibody testing
before the drug is started in MS patients. The risk of PML is believed
to be virtually nil for
patients without JC virus infection, but false-negative serological
test results would lead to incorrect PML risk prediction.
"To
establish risk-stratification algorithms for PML in patients who
receive potent immunomodulatory therapies, a single measurement of viral
activity, such as a test for antibodies to JC virus, may be useful but
not sufficient to assess risk," the researchers wrote. They recommended
"a more comprehensive risk-mitigation strategy" that involves periodic
testing during natalizumab treatment.
Natalizumab's
label now calls for repeat serology testing every 6 months, citing the
risk of new JC virus infections that may occur during treatment.
Infections are relatively common in the general population. In the
current study, 12 of the 18 healthy volunteers were seropositive.
On
the other hand, a positive test result is not an absolute
contraindication to natalizumab. "The risks and benefits of continuing
treatment with Tysabri should be carefully considered in patients who
are found to be anti-JCV antibody positive and have one or more
additional risk factors," it says. Such risk factors include duration of natalizumab therapy and prior history of immunosuppressant treatment.
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